Inhibitory Pathways Triggered by ITIM-Containing Receptors

ADVANCES IN IMMUNOLOGY. VOL 72

Inhibitory Pathways Triggered by ITIM-Containing Receptors SllVlA B O U N D AND JEFFREY V. RAVETCH f i e Rockefeller Uniersify, New York, New Yo& 10021

1. introduction

Cell activation triggered by immune receptors, such as the B cell, T cell, or Fc receptor (BCR, TCR, or FcR), display the capacity to undergo fine modulation to adjust to different developmental and environmental conditions. The response to a particular stimulus represents the balance between stimulatory and inhibitory signals and its magnitude will determine the fate of the cell. Thus, the strength of BCR stimulation determines whether a particular cell will proliferate or enter an apoptotic pathway (Nossal, 1994; Rajewsky, 1996; Healy and Goodnow, 1998). Similarly, TCR stimulation can result in either positive or negative selection, determined by the signal intensity transduced through the receptor (Hogquist et al., 1994; Sebzda et al., 1994).Regulation of the immune response also requires the termination of activation signals when the response has met the immediate need. For example, Fc receptor coligation to the BCR by antibodyantigen complexes abrogates B cell proliferation and antibody secretion, terminating the activation response that sets the program in motion (Ravetch, 1994,1997; Daeron, 1997).An important element in this fine-tuning of cell signals is the newly discovered class of inhibitory receptors, which modulate cell responses by increasing thresholds for activation and terminating stimulatory signals. The characterization of several inhibitory receptors in recent years has permitted the identification of a family of receptors that reveal similar characteristics (Vivier and Daeron, 1997;Vely and Vivier, 1997). These receptors are inert when self-aggregated but are able to abolish cellular signals when coligated to stimulatory receptors. Their cytoplasmic domains contain one or more immune receptor tyrosinebased inhibitory motifs (ITIMs), defined by the six-amino acid sequence (ILV)xYxx(LV)(Vivier and Daeron, 1997; Burshtyn et al., 1997; Vely and Vivier, 1997). In a number of cases, ITIM sequences have been shown to be phosphoylated on receptor coligation to create a binding site for Srchomology 2 (SH2) domain-containing cytoplasmic factors that can transmit the inhibitory signal intracellularly (Muta et al., 1994; Fry et al., 1996; Olcese et al., 1996; Burshtyn et al., 1996; Mason et al., 1997; Nakamura et al., 1997; Kuroiwa et al., 1998; Adachi et al., 1998). The ITIM-bearing receptors commonly inhibit activating signals triggered by receptors that contain the immune receptor activation motif 149

Copyright 6 1989 by Academic Press. All rights of reproduction in any fonn reserved. 0065-2776/99 $30.00

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(ITAM) in their cytoplasmic tails, such as the BCRs, TCRs, and FcRs. Cell activation mediated by ITAM-containing receptors involves the phosphorylation and activation of several tyrosine kinases and subsequent activation of phospholipase Cy and phosphatidylinositol 3-kinase (PLCy and PI3-K), together leading to the production of phosphoinositol messengers and a sustained increase in cytoplasmic Cazt (Bijsterbosch et al., 1985; Weiss and Littman, 1994;Alberola-Ilaet al., 1997) (Fig. 1A). It has become evident in the past few years that inhibitory receptors use two different strategies to terminate cell activation depending on the type of molecule that is recruited to the phosphorylated ITIM sequences (Gupta et al., 1997; Ono et al., 1997; Vely et al., 1997). Inactivation can be attained by protein dephosphorylation mediated by the tyrosine phosphatases SHP-1 and/or SHP-2, in which case the most proximal events in the activation cascade are abrogated so that Ca2+mobilization is completely abolished (Fig. 1B). A second mode of inhibitory signal utilizes the phosphoinositol phosphatase SHIP to hydrolyze phosphoinositol messengers (Fig. 1C). This type of inhibitory signal does not affect proximal events triggered by the activating receptor, such as the activation of kinases, receptor phosphorylation, or Ca2+release from intracellular stores, but it specifically impedes extracellular Ca2+influx and therefore blocks a sustained increase in cytoplasmic Ca". Analyses of the mechanism of action of FcyRII and KIR, the best studied inhibitory receptors to date, show that they utilize distinct and nonredundant pathways. Although the FcyRII signal is dependent on the phosphoinositol phosphatase SHIP and not the tyrosine phosphatase SHP-1, the KIR signal is dependent on SHP-1 and not SHIP (Gupta et al., 1997; Ono et al., 1997; Vely et al., 1997). Thus, there is fine specificity regarding which events are inhibited by each receptor so that the type of inhibitory receptor engaged in a particular situation will determine the kind of suppression that is achieved. The three molecules recruited by inhibitory receptors, SHP-1, SHP-2, and SHIP, are part of the general regulation of immune receptor activation. They have been found associated with antigen, Fc, growth factor, and cytokine receptors and their absence results in augmented cell activation and proliferation (Tsui et al., 1993; Pani et al., 1995, 1996; Cyster and Goodnow, 1995; Lioubin et al., 1996; Helgason et al., 1998). Thus, they not only function through recruitment to inhibitory receptors, but also via association with stimulatory receptors to set thresholds or to prevent unsolicited cell activation. II. Inhibitory Receptors and Activating Counterparts

The family of inhibitory receptors is expanding rapidly; at least 14 families of receptors have been found that contain one or more ITIM motifs in

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FIG. 1. Schematic representation of immune receptor signaling pathways. (A) Crosslinking of activating immune receptors leads to ITAM phosphorylation and recruitment of protein kinases via SH2 domain interactions. Membrane association of PIS-kinase results in the production of PIP3 and recruitment of PH domain-containing factors such as Btk and PLCy. Both Src kinases and Btk phosphorylate PLCy. Activated PLCy produces IP3, the release of intracellular Ca2+,and subsequent Ca2+influx from the extracellular medium. (B ) Coengagement of the KIR inhibitory receptor completely abolishes Ca" mobilization triggered by immune receptor cross-linking. KIR-phosphorylated ITIM sequences recruit the tyrosine phosphatase SHP-1, which dephosphorylates receptor ITAMs and associated kinases, abrogating all the proximal events in the activation cascade. (C) Coengagement of

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FIG. l-Continued FcyRII inhibitory receptor abrogates Ca2+influx but does not impede Ca2+release from intracellular stores. FcyRII-phosphorylated ITIM recruits SHIP, which hydrolyzes PIP3 into PIP2, and impedes the recruitment to the membrane of PH domain-containing factors such as Btk and PLCy.

their intracellular domains, as listed in Table I. Inhibitory receptors have been identified in all types of hematopoietic cells and also in some nonhematopoietic cells. Structurally, they are single-chain receptors that belong to the immunoglobulin or the lectinlike superfamilies. A few of them are expressed at the surface as homodimers (p70 KIR, Ly-49, CD72) or heterodimers (CD94NKG2A). Details of the different receptors and their ligands have been discussed in previous publications (Orourke et al., 1997; Daeron, 1997; Lanier, 1997,1998a,b; Moretta et al., 1997;Vely and Vivier, 1997). An interesting point is that inhibitory receptors have an activating receptor counterpart that contains a highly homologous extracellular domain and a short cytoplasmic portion that lacks signaling capacity. The transmembrane domains of these activation receptors are characterized by the presence of a charged amino acid, a hallmark of receptors that associate with accessory subunits containing the activation ITAM motif (Vely and Vivier, 1997). At the present time three such accessory subunits have been identified: the FcR y chain, the CD3 chain, and DAP-12 (Kurosakiet al., 1991;Wirthmueller et al., 1992; Olcese et al., 1997; Smith et al., 1998; Lanier et al., 1998a,b).These molecules are structurally related, with a short extracellular sequence containing a cysteine residue that medi-

TABLE I INHIBITORY RECEPTORS Class Ig-SF

Receptof

Ligand

Activating partner

Expression

Ref.

(nl/h)FryRIIB

ITYSLL

IgG complex

FcyRIII

Myeloid and B cells

(h)KIR (p58/p70)

VTYAQL IVYELL VTYAQL VTYAEV VTYAQV VTYAQL ITYAAV IVYAQV VTYAQL ITYADL LTYADL VSYAIL IHYSEL VDYVTL VTYSTL IIYSEV

HLA-A, -B, -C

KAR

NK and T cells

Unhown HLA-G

PIR-A ILTl

Myeloid and B cells All immune cells

Aniigorena et al. (1992), Muta et al. (1994) Colonna and Samaridis (1995), D'Andrea et al. (1995) Kubagawa et al. (1997) Samaridis and Colonna (1997)

Unlolown

-

T and NK cells

Meyaard et al. (1997)

Unknown

-

Myeloid and NK cells

Castells et al. (1994)

Hematopoietic and nonhematopoietic cells B cells

Kharitonenkov et al. (1997)

(m)PIR-B (h)ILT2/3/4/5 (h)LAIR-l (m)gp49B1 (h)SIRPa (mn/h)CD22 (m/h)CD66a

Lectinlike

ITIM sequence

(m)CD5 (m/h)CTLA-4 (m)Ly49A/C/G2 (h)NKG2A/B (di)CD72

-b -I,

VTYSTV

VIYSDL ITYAEL ITYADL ITYENV

Growth factor Sialic acid Unknown CD72 CD80, CD86 MHC I HLA-E, -G CD5

SIRPP -

CD66d -

Ly49D/H NKG2C -

Doody et al. (1995)

QZ. (1991)

Neutrophils and embryonic cells T and B cells T cells NK and T cells NK and T cells

Van de Velde et QZ. (1991) Brunet et al. (1987) Yokoyama and Seaman (1993) Chang et ~ 2 (1995) .

B cells

Nakayama et al. (1989)

* m, mouse; 11, human. 'These receptors have no canonical ITIM motif in their cytoplasmic domains, but have been sbown to be inhibitory.

Thompson et

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ates the formation of homo- or heterodimers with related accessory subunits, a charged amino acid in the transmembrane domain, and an intracytoplasmic sequence containing one or more ITAM motifs. They function both in receptor assembly and signal transduction. Absence of the accessory subunit results in little or no surface expression of the ligand-binding subunit, whereas the ITAM motif is required for mediating cellular activation on receptor cross-linking. In those cells in which both activating and inhibitory receptors with homologous extracellular domains are present simultaneously,the relative expression level of the two receptors will determine the activation state of the cell. For example, the FcyRIIB/FcyRIII pair is present on mast cells, macrophages, and neutrophils. Both receptors bind immunoglobulin G (IgG) immune complexes with low affinity, so that cells that express low levels of the inhibitory receptor FcyRIIB, such as skin mast cells or alveolar macrophages, are very responsive to the presence of immune complexes, whereas cells that express high levels of FcyRIIB, such as bone marrow-derived mast cells or resident macrophages, are relatively unresponsive (Bonnerot and Daeron, 1994; Castells, 1994; Katz and Lobell, 1995; Daeron, 1997; R. Clynes and J. V. Ravetch, unpublished). In the same way, natural killer (NK) cells can express many combinations of activating or inhibiting receptors, some of which will recognize the same HLA allele (Biassoni et al., 1996). How inhibitory and activating major histocompatability complex (MHC) class I receptors interact to regulate the activity of NK cells is not clear at the moment. At the very least, the function of activating receptors should be to recruit kinases that phosphorylate ITIMs on the inhibitory receptor. The overall cell response in this case seems to be the inhibition of NK cytotoxicity as a result of the dominant signal coming from the inhibitory receptor. The PIR family of surface receptors represents another example of this dichotomy of activation and inhibitory receptors expressed on the same cells. They include the activation molecule PIR-A, which associates with the FcR y chain as its activatory subunit, and the homologous PIR-B inhibitory receptor (Maeda et al., 1998a; Kubagawa et al., 1997, 1998; Blery et al., 1998). The ligands for these molecules have not been identified, but the presence of both activation and inhibitory molecules with highly homologous extracellular domains suggests that they function in concert to set thresholds for lymphoid and myeloid cells. 111. FcflI-Mediated Inhibitory Signal

FcyRIIB is a low-affinity receptor for the Fc portion of immunoglobulin G, with IgG immune complexes as its natural ligands (Ravetch and Kinet, 1991). It is a widely expressed receptor, present on all hematopoietic

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lineages with the exception of red blood cells and NK cells. FcryRII was the first receptor known to abrogate cellular responses when coligated to an activating receptor. Its function was initially characterized in B cells, where it modulates antibody production, lymphokine release, and cell proliferation. It was known for a long time that immune complexes are strong inhibitors of humoral immune responses (Chan and Sinclair, 1971). Initial evidence for the involvement of FcyRII in this immune complexmediated regulation of B cell activationwas provided by Phillips and Parker (1983, 1984), who established that although F(ab')e fragments of anti-Ig antibodies (Abs) induced B cell proliferation, intact IgG Abs did not. This experiment implicated an FcR, later defined as FcyRIIB, the only IgGFc binding molecule on B cells, in the inhibitory effect of intact IgG. The ITIM sequence was first defined after the identification of a 13amino acid sequence (EANTITYSLLKH) in the cytoplasmic domain of FcyRII that is required for negative signaling (Amigorena et al., 1992). Muta et al. (1994) formally demonstrated that this ITIM sequence is sufficient for inhibitory signaling when it is expressed in an inert receptor context and that a tyrosine included in the sequence is essential for FcyRIImediated inhibitory signaling. On BCR coligation, the ITIM on the FcyRII cytoplasmic portion is phosphorylated on Tyr-309 by the BCR-activated 1p kinase (Wang et al., 1996; Malbec et al., 1998). This phosphorylation event creates a domain recognized by SH2-containing molecules and suggested that the mechanism of inhibition by FcyRIIB is mediated by the recruitment of such a molecule to the membrane. The molecular mechanism of the FcyRII inhibitory signal has been best studied in B cell lines. Antigen-mediated aggregation of the BCR promotes several distinct intracellular pathways, yet there is fine specificity as to which ones are subject to inhibition by FcyRII. BCR cross-linking induces the tyrosine phosphorylation of many proteins, including associated receptors CD19 and CD22, the BCR signaling chains Iga and I& the kinases Syk, lyn, PI3-K, and Btk, and other factors such as PLCy, Shc, Grb2, and Vav (Bijsterbosch et al., 1985; Tuveson et al., 1993; Weng et al., 1994; Takata et al., 1994, 1995; Zhang et al., 1995; Doody et al., 1995; Takata and Kurosaki, 1996; Smit et al., 1996; Yamanashi et al., 1997; Sugawara et al., 1997; Kurosaki, 1997). Activated PLCy generates inositol3-phosphate (IP3) and triggers Ca2+ release from intracellular stores. Depletion of Ca2+from intracellular stores stimulates Ca" influx from the extracellular medium by an unknown mechanism. Altogether, the sustained increase in cytoplasmic Ca2+results in the transcriptional activation that leads to proliferation and/or differentiation of the cells (Dolmetsch et al., 1997). Simultaneous coligation of FcyRII with the BCR leads to a dominant negative signal that inhibits some of these events. Although there is no

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change in phosphorylation of the activated kinases and CaZt release from intracellular stores, there is a blockage at the Ca2+influx stage with consequent arrest of transcriptional activation and cell proliferation and/or differentiation (Choquet et al., 1993; Muta et al., 1994). Because FcyRII inhibition does not completely abrogate BCR-triggered Ca" mobilization, it might selectively inhibit transcription pathways that require high Ca2' levels for activation, For example, it has been reported that the amplitude and duration of Ca2' signals in B cells control differential activation of NF-KB, JNK1, and NFAT (Dolmetsch et al., 1997). Selective inhibition of transcription pathways could be a way to allow the necessary stimulation for B cell survival without inducing cell proliferation. In vitro, the FcyRII-phosphorylated ITIM can bind to three different SH2-containing molecules: the tyrosine phosphatases SHP-1 and SHP-2, and the phosphoinositol polyphosphate phosphatase SHIP (D'Ambrosio et al., 1995; Ono et al., 1996). The role of these three phosphatases in FcyRII-mediated signaling in uivo has been the subject of some controversy. SHP-1 has been proposed as the mediator of FcyRII inhibitory signaling via its direct effect on the phosphorylation of CD19, a BCRassociated coactivator (Hippen et al., 1997). CD19 dephosphorylation by SHP-1 has been proposed as a mechanism that would lead to a decrease in PI3-K recruitment and abrogation of cell activation (Tuveson et al., 1993). Several lines of evidence argue against this conjecture. First, bone marrow-derived mast cells from moth-eaten mice (melme),which are naturally deficient in SHP-1, still show FcyRII-mediated inhibition of FcRtriggered degranulation (Ono et al., 1996). Moreover, a B cell line derived from m e l m lymphocytes retains FcyRII-mediated inhibition of BCRtriggered activation. Experiments using this cell line established that SHP1 is not required for the FcyRII-evoked decrease in CD19 tyrosine phosphorylation (Nadler et al., 1997). Although it is still formally possible that the tyrosine phosphatase SHP-2, which binds in uitro to the phosphorylated ITIM, can substitute for SHP-1 in this role, this is unlikely. FcyRII signaling is functional in the chicken B cell line DT40, deficient for both SHP-1 and SHP-2 (S. Bolland and J. V. Ravetch, unpublished). Altogether, these genetic studies provide strong evidence against a prominent role for tyrosine phosphatases in the mechanism of FcyRII inhibition of Ca2' signals. Out of the three SH2-containing phosphatases capable of interaction with the phosphorylated ITIM of FcyRIIB, SHIP seems to be the molecule preferentially recruited to the cytoplasmic domain of FcyRII in uiuo, as demonstrated by immunoprecipitation following coligation to the BCR or to FcsRI (Ono et al., 1996, 1997; Fong et al., 1996). Genetic proof of the significance of this association came from a DT40 SHIP knockout cell line, which is impaired for FcyRILmediated inhibition of BCR-triggered Ca2+

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mobilization, clearly demonstrating that SHIP protein is necessary for this pathway (Ono et al., 1997). As will be summarized below, SHIP-deficient murine B cells display a similar phenotype, further confirming the biological relevance of the association of SHIP with FcyRIIB in mediating the inhibitory effect of this receptor (Liu et al., 1998). Characterization of mice with disruption of the FcyRIIB gene has helped to further elucidate the biological function of this inhibitory receptor (Takai et al., 1996).Developmental defects were not noted, nor were autoantibodies detected. Antibody responses are enhanced in these mice, which have serum antibody titers 3-10 times higher following immunization with both T cell-dependent and T cell-independent antigens. This response confirms FcyRII as a modulator of B cell antibody production. However, based on in vitro studies, the magnitude of this enhancement is not as substantial as was expected, a fact that can be explained in several ways. FcyRII is expressed in cells other than B cells, which are involved in modulating the antibody response. For example, follicular dendritic cells ( FDCs) express FcyRII as their sole FcR, functioning in the retention of antigen as immune complexes. This positive role in shaping the B cell repertoire through positive selection of high-affinity BCRs could therefore counterbalance the negative effect of FcyRII on B cells. Furthermore, FcyRII might modulate responses of naive B cells but not cells that establish the extent of antibody responses, such as memory B cells or plasma cells. The FcyRIIdeficient mice display a defect in the primary antibody response, with elevated serum titers of IgM as well as IgG, supporting the hypothesis that this receptor has a pleiotropic role in regulating the antibody response. Obviously, the presence of additional regulatory pathways still active in the FcyRII-deficient B cells cannot be dismissed. In addition to the inhibitory function on B cell activation, FcyRII can also inhibit activation signals in many other hematopoietic cells where it is expressed. It has been shown to inhibit FcR-triggered mast cell degranulation when coligated to FcyRIII or FceRI (Daeron et al., 1995a,b).Accordingly, mice deficient in FcyRII are hyperresponsive for peripheral cutaneous anaphylaxis (PCA) to IgG complexes (Takai et al., 1996). These mice also seem to exhibit enhanced responses in various models of inflammation, such as immune complex-induced alveolitis, collagen-induced arthritis, and systemic anaphylaxis, confirming that FcyRII functions to set thresholds for immune complex stimulation in systems in which FcyRIII is the primary effector (Clyneset al., 1998; Ujike et aZ., 1999;Yuasa et al., 1999).Moreover, FcyRIIB-deficient mice display an enhanced sensitivity to IgE-mediated systemic anaphylaxis, indicating an unexpected interaction between FcERI and FcyRIIB in setting thresholds for IgE-triggered mast cell activation. This enhanced IgE-mediated response may result from the ability of IgE

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to interact with FcyRII with low affinity, or it may result from competition between FceRI and FcyRII for SHIP, thereby altering the threshold for stimulation. As described below, the SHIP-deficient mouse displays a similar enhancement of IgE signaling (Helgason et al., 1998). IV. Mechanism of Inhibition by SHIP

The SH2-containing inositol 5-polyphosphate phosphatase SHIP has been recognized as a general regulator of immune receptor activation, in addition to its role in mediating FcyRII inhibitory signaling. SHIP is widely expressed in all hematopoietic lineages and functions to set thresholds in a variety of systems such as growth factor-induced cell proliferation and antigen receptor or FcR stimulation (Damen et al., 1996; Lioubin et al., 1996; Kavanaugh et al., 1996;Ono et al., 1996). It is a 145-kDa protein with multiple domains that can potentially signal through several intracellular pathways and provide diverse protein interactions. It contains an aminoterminal SH2 domain that binds to phosphotyrosine receptors and mediates recruitment to the membrane. This domain has been reported to interact with the phosphorylated ITIM from FcyRII, as well as the phosphorylated ITAMs from FcERI p chain and TCR-J chain (Crowley et al., 1996; Osborne et al., 1996; Kimura et al., 1997a). In addition, SHIP contains two tyrosine residues that, in the phosphorylated form, can bind phosphotyrosine-binding (PTB) domain-containing molecules, such as the adapter molecule Shc or the tyrosine phosphatase SHP-2 (Liu et d., 1994, 1997; Kavanaugh et al., 1995; Lamkin et al., 1997; Pradhan and Coggeshall, 1997). Its catalytic domain contains inositol polyphosphate 5-phosphatase motifs; this enzymatic activity has been observed in immunoprecipitates of SHIP alone, or SHIP associated with Shc or FcyRII (Jefferson and Majerus, 1995; Damen et al., 1996; Lioubin et aZ.,1996; Ono et al., 1996). Finally, the proline-rich carboxy-terminaldomain of SHIP could potentially interact with any of the reported SH3 domain-containing proteins. SHIP has been found to be tyrosine phosphorylated and associated with Shc following activation of receptors for numerous cytokines including erythropoietin (Epo), c-Kit, interleukin 3 (IL-3), IL-2, granulocyte/macrophage colony-stimulating factor (GM-CSF), and M-CSF (Liu et al., 1994, 1996; Damen et al., 1996; Hunter and Avalos, 1998). SHIP is also phosphorylated following cross-linking of antigen receptors in B and T cells or following activation of FceRI in mast cells (Chacko et ab., 1996; Osborne et al., 1996; Pradhan and Coggeshall, 1997). SHIP phosphorylation can occur as a consequence of its recruitment nearby an activating receptor. It is also possible that SHIP is constitutively associated with some receptors, so that upon receptor cross-linking SHIP becomes phosphorylated, associatedwith

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Shc, and at the same time dissociated from the receptor. In this context, SHIP would function as a gatekeeper to avoid unintentional activation. So far, there is no clear evidence to show that phosphorylation affects SHIP activity, or its recruitment to the membrane. Nevertheless, SHIP has been proposed to be a down-modulator of cell activation because its overexpression causes inhibition of cell growth (Lioubin et al., 1996). More detailed investigations have arisen from the analysis of the SHIPmediated inhibitory signal triggered by FcyRII coligation. In this case, SHIP protein is sufficient to abrogate the Ca2+influx triggered by BCR cross-linking, as evidenced by a chimeric receptor that substitutes the FcyRII cytoplasmic portion for SHIP and is competent for inhibitory signaling (On0 et al., 1997). Mutation of the inositol phosphatase motif in this construct abolishes the inhibitory function, implying that the enzymatic activity of SHIP is necessary for inhibition of Ca" influ. SHIP catalyzes the hydrolysis of the 5'-phosphate of two specific substrates: inositol1,3,4,5tetrakisphosphate (IP4) and phosphatidylinositol3,4,5-trisphosphate (PIP3 or PIns3,4,5P3) (Damen et al., 1996; Lioubin et al., 1996). IP4 is a cytosolic inositol phosphate that has been shown to activate certain plasma membrane Ca" channels (Luckhoff and Clapham, 1992). PIP3 is a membranebound phosphoinositol that has been observed to appear after stimulation of virtually every receptor type (Traynor-Kaplan et al., 1988; Auger et al., 1989; Coughlin et al., 1989; Backer et al., 1992; Carpenter and Cantley, 1996; Toker and Cantley, 1997). Thus, both the hydrolysis of IP4 and of PIP3 by SHIP could have an inhibitory effect on receptor-triggered Ca" mobilization. PIP3 has already been observed to be involved in immune receptor-triggered activation signals, because it is originated from PIns4,5P2 by PI3-K, an enzyme recruited and activated by ITAM crosslinking (Tuveson et al., 1993; Pleiman et al., 1994; Gold and Aebersold, 1994; Ward et al., 1996; Aagaard-Tillery and Jelinek, 1996). PIP3 has been proposed to interact with proteins that contain a plecstrin-homology (PH) domain to promote their association with the plasma membrane and place them in proximity to their substrates (Lemmon et al., 1996). Examples of such PH domain-containing factors that have been shown to bind PIP3 in vitro are PKC, PDK1, Grpl, PLCy, and the Btk/Itk/Tec kinases (Nakanishi et al., 1993; Toker et al., 1994; Kojima et al., 1997; Rameh et al., 1997). SHIP, by reducing the levels of PIP3, can prevent the recruitment to the membrane of these molecules, and in this way can abrogate cellactivating signals. The necessity of PH domain-mediated recruitment to the membrane has been extensively analyzed in the case of Bruton's tyrosine kinase (Btk). Spontaneous mutations in this protein are responsible for X-linked agammaglobulinemia in humans and X-linked immunodeficiency in mice (Smith

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et al., 1994; de Weers et al., 1994), in both cases demonstrating that Btk is necessary for B cell development and activation. Some of these spontaneous mutations alter the PH domain of Btk such that it is no longer able to bind PIP3. These mutations generate cells that are compromised in mediating BCR-triggered cellular activation (Salimet al., 1996; Hyvonen and Saraste, 1997). Conversely, mutations in the Btk PH domain that lead to increased membrane association display enhanced Ca2+mobilization on BCR cross-linking (Li et al., 1995). When overexpressed, Btk enhances the sustained increase in cytoplasmic Ca2+following BCR cross-linking, affecting mostly the Ca2+influx step (Bolland et al., 1998; Fluckiger et al., 1998). This enhancement in Ca2+mobilization is even larger when Btk is expressed as a membrane chimera, probably because of the proximity to its substrate. Therefore, PIPS-dependent membrane recruitment of Btk is essential to maintaining the sustained Ca" responses required for B cell activation. SHIP enzymatic activity, by reducing the PIP3 levels, can impair Btk recruitment to the membrane and the sustained Ca2+response. In fact, the inhibitory effect of FcyRII or SHIP can be suppressed by expression of Btk as a membrane-associated chimera, and pathways that result in decreased PIP3 levels reduce Btk membrane association and accordingly reduce Ca" mobilization. Meanwhile, cells deficient in SHIP show a higher level of Btk associated with the membrane and a concomitant enhancement of Ca2' mobilization following BCR cross-linking (Bolland et al., 1998). Although Btk is primarily expressed in B and mast cells, additional tyrosine kinases with significant homology to Btk are expressed in both hematopoietic and nonhematopoietic cells. Examples include Itk, with expression restricted to T, NK, and myeloid cells, and the kinase Tec, present in myeloid cells and nonimmune tissues (Siliciano et al., 1992). Itk has been observed to be recruited to the membrane through PH domain interactions following TCR activation (August et al., 1997). Because SHIP is widely expressed in myeloid and lymphoid cells, it is conceivable that its inhibitoly function regulates membrane association of Btk homologs in the same manner as observed for Btk in B cells. In addition to attenuating the recruitment of Tec kinases, SHIP could also have an effect on PLCy PHmediated membrane recruitment and activation,thereby reducing IP3 production. Membrane-associated Btk could affect Ca" influx directly by acting on the Ca2+channel, or indirectly through phosphorylation of an intermediate. Several proteins have been reported to associate with Btk: PLCy, G protein /3/y subunits, protein kinase C, and two novel proteins of unknown function, BAP-135 and Sab (Langhans-Rajasekaranet al., 1995; Yang and Desiderio, 1997; Yao et al., 1997; Matsushita et al., 1998). Some of these factors could be substrates of the Btk kinase activity: tyrosine phosphorylation of PLCy2,

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for example, has been shown to be partly mediated by Btk. In DT40 B cells deficient in Btk, PLCy phosphorylation is less intense following BCR cross-linking.Conversely, PLCy phosphorylation is enhanced when cotransfected with Btk and PI3-K (Scharenberget al., 1998). Btk-mediated stimulation of PLCy activity should result in increased IP3 levels, complete Ca2+depletion of intracellular stores, and concomitant enhancement of Ca" influx. Consistent with this hypothesis, IP3 production triggered by BCR cross-linking in DT40 cells is completely dependent on Btk (Takata and Kurosaki, 1996). Remarkably, FcyRII-mediated inhibitory signaling does not completely abrogate PLCy or Btk activity, because Ca" release from intracellular stores seems unchanged. This suggests that SHIP activity can prevent Btk and/or PLCy recruitment to the membrane but does not completely abrogate their activity. V. Inhibition by KIR Receptors

Experiments on the rejection of autologous tumors in mice provided the first indication that NK cells eliminate cells that have lost expression of MHC class I molecules (Karre et al., 1986). Subsequent experiments showed that NK cells recognize MHC class I molecules with allele specificity and clonal diversity (Moretta et al., 1990). This finding predicted the existence of multiple NK cell receptors that recognize polymorphic MHC determinants and transmit an inhibitory signal to prevent NK cell-mediated killing. Since then, several families of inhibitory receptors with specificity for MHC class I molecules have been identified, all of them containing ITIM sequences in their cytoplasmic tails. Human NK cells express p58 and p70 KIRs, which contain two and three Ig domains in their extracellular portion, respectively (Moretta et al., 1993; D'Andrea et al., 1995; Colonna and Samaridis, 1995). These cells also express the lectinlike family of receptors NKG2, including the inhibitor receptor NKGSA, which forms heterodimers with CD94 (Chang et al., 1995; Brooks et al., 1997; Carretero et al., 1997). The murine form of NK inhibitory receptor is the lectinlike Ly49 family (Karlhofer et al., 1992; Yokoyama and Seaman, 1993). Each of the NK cell inhibitory receptors abrogates cytotoxicity when coligated with ITAM-dependent receptors such as FcyRIII or any of the activating isoforms of p50 (KAR), Ly49, and NKG2 (Fry et al., 1996; Houchins et al., 1997). Signals triggered by these receptors are very similar to the antigen receptor-mediated activation of B or T cells. They engage PLCy to produce IP3, which stimulates Ca2+mobilization from intracellular stores and subsequent extracellular Ca" influx (Azzoni et al., 1992; Ting et al., 1992; Kaufman et al., 1995). Simultaneous cross-linking of the inhibitory receptors results in the tyrosine phosphorylation of the

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cytoplasmic tail of KIRs (Campbell et at., 1996; Fry et at., 1996; Olcese et al., 1996; Burshtyn et al., 1996). Human KIRs contain two ITIM sequences in their cytoplasmic domain. Each of these ITIMs, in its phosphorylated form, can bind in vitro to SHP-1 and SHP-2, but not to SHIP (Vely et al., 1997). It follows that SHIP has additional sequence requirements other than the ITIM motif WxYxxL. It also seems that in most cases SHP1 prefers the sequence VxYxxL. The N-terminal ITIM (VTYAQL) binds to both of the SHP-1 SH2 domains, and it does it more efficiently than the C-terminal ITIM (IWELL). The N-terminal ITIM has been found to be sufficient for the inhibitory signal in deletion studies (Fry et al., 1996). Out of the two SH2 domains of SHP-1, the N-proximal one not only acts as a recruitment unit, but also as a regulator of SHP-1 phosphatase activity (Pei et al., 1994, 1996). Indeed, phosphorylated ITIMs have been reported to activate the SHP-1 tyrosine phosphatase function (D’Ambrosio et al., 1995). It remains to be determined if both ITIMs in KIR simultaneously bind the two SHP-1 SH2 domains in physiological conditions, or whether SHP-1 and SHP-2 can conjointly bind the KIR cytoplasmic tail. Evidence for a definitive role of SHP-1 in KIR-mediated inhibitory signaling came from experiments showing that overexpression of a dominant negative SHP-1 mutant in NK cell clones prevents MHC class Imediated inhibition of NK cell lysis (Burshtyn et al., 1996). This point was genetically tested by the analysis of DT40 cells deficient in SHP-1. A chimeric receptor containing the cytoplasmic portion of human KIR (p58) was shown to inhibit BCR-triggered activation in DT40 wild-type and SHIP-’- cells, but not in SHP-l-’- cells (On0 et al., 1997). In these experiments, a chimeric receptor containing SHP-1 in the cytoplasmic portion was found to be sufficient to deliver an inhibitory signal and dependent on the phosphatase catalytic domain. So far, the direct substrates of SHP1 activity have not yet been definitively identified. Studies of target cells protected from NK lysis by expression of KIRs have detected a reduction in CD3 chain and PLCy phosphorylation and the absence of PIP2 hydrolysis, all of which abrogate Ca2+mobilization completely (Kaufman et al., 1995; Binstadt et al., 1996; Blery et at., 1997). Other factors that have been found associated with SHP-1 are ZAP-70, Lck, and Src kinases (Plas et al., 1996; Raab and Rudd, 1996; Somani et al., 1997). It is likely that SHP-1 acts to dephosphorylate, in a nonspecific manner, several of the factors involved in NK activation signaling. Whether the signal is completely abrogated will depend on the time required to recruit and activate SHP-1, which in some cases will allow an initial spike of activation. Many inhibitory receptors other than KIRs seem to recruit SHP-1 and/ or SHP-2 for signaling. Phosphorylated ITIMs from gp49B1, CD22, CD66, CD72, Ly-49, ILT-2, ILT-3, LAIR-1, NKG2-A, and PIR-B have been

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found associated with SHP-1 and SHP-2 (Doody et al., 1995; Mason et al., 1997; Nakamura et al., 1997; Blery et al., 1998; Ledrean et al., 1998; Adachi et al., 1998; Carretero et al., 1998; Maeda et al., 199813).Phosphory-

lated ITIMs from gp49B1 and PIR-B also bind SHIP, although their inhibitory function seems unaffected in the DT40 SHIP-’- cells (Kuroiwa et al., 1998; Maeda et al., 199813). VI. Lessons from SHIP, SHP-1,and SHP-2 Knockout Mice

The naturally occumng mutation of the SHP-1 gene is the primary gene defect in moth-eaten (me)mice (Tsui et al., 1993; Shultz et al., 1993). These mice suffer from severe combined immunodeficiency in association with an autoimmune syndrome, and usually die of pulmonary complications within the first weeks of life. The me phenotype is characterized by extensive neutrophilic infiltration of dermal tissues and accumulation of macrophages and granulocytes in the lung, with markedly reduced lymphocyte populations in the bone marrow. The development of systemic autoimmunity in these mice can be explained as a consequence of an abnormal expansion of the B-1 subset that results in the production of autoantibodies. In addition to these obvious abnormalities, in vitru experiments have shown that bone marrow macrophages from me mice grow independently of CSF1, and that B and T cells are hyperresponsive to antigen cross-linking. In general, this phenotype is consistent with the absence of a major regulator of immune cell signaling that controls the growth and development of a large variety of hematopoietic cells. Because SHP-1 has been observed associated with several cytokine and antigen receptors (Yi et al., 1993b; Klingmuller et al., 1995; Pani et al., 1995, 1996; Konkozlowski et al., 1996; Paulson et al., 1996; Lopez et al., 1997; Yu et al., 1998; Kozlowski et al., 1998), it is likely that the pleiotropic phenotype in me mice results from multiple primary cell defects. The phenotype of the SHIP-deficient mouse is remarkably similar to the moth-eaten phenotype. Absence of SHIP results in a myeloproliferative-like syndrome, with profound splenomegaly and massive myeloid cell accumulations in the lungs that lead to death at approximately 10 weeks of age (Helgason et al., 1998). In addition, peripheral blood from SHIP-’mice contains an increased number of circulating monmytes and mature neutrophils, with decreased lymphocyte counts. In vitro, bone marrow progenitors exhibit an enhanced sensitivity to GM-CSF and IL-3, and mast cells from SHIP-’- mice are hyperresponsive to Fc receptor activation. Also, SHIP-deficient DT40 B cells are hyperresponsive to BCR stimulation, confirming SHIP as a general regulator of B cell activation (Bolland et al., 1998). The lymphopenia observed in the SHIP knockout mouse could

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then be explained because of excessive signaling through the BCR that negatively selects SHIP-/- cells. Accordingly, SHIP-deficient B cells obtained by RAG-’- blastocyst complementation are hyperresponsive to BCR activation and show abnormal differentiation (Liu et al., 1998). The similarities between SHIP- and SHP-l-deficient mice suggest that these two molecules regulate equivalent activating signals in the same cell types. Both are widely expressed in the immune system, are recruited by SH2 domain interactions, and have been found associated with the same stimulatory receptors, such as IL-3, c-Kit, CSF, FceRI, TCR, BCR, or erythopoietin receptor (Yi and Ihle, 1993;Yi et al., 1993,1995; Klingmuller et al., 1995; Pani et al., 1995; Lorenz et al., 1996; Kimura et al., 1997b),This raises the question of whether SHIP and SHP-1 function independently, in a redundant manner, or with complementary functions. The fact that deficiencies in either of them result in a marked phenotype argues against redundant functions. Most likely, SHIP and SHP-1 act simultaneously to prevent unintentional cell activation,but neither of them alone at physiological levels is sufficient to provide full repression. Coengagement of a particular inhibitory receptor might specifically recruit SHIP or SHP-1, so that the local concentration of that factor is increased and full inhibition of specific pathways is achieved. Despite the similar phenotypes in deficient mice, SHIP and SHP-1 modulate activation responses in significantlydifferent ways, suggesting that in a normal physiological context, the type of inhibitory signal will be important. Because the perturbations in these molecules result in pleiotropic effects, conditional deficiencies will need to be generated and analyzed to determine the consequence of each pathway in modulating activation signals. The phenotype of SHIP and SHP-1 knockout mice is reminiscent of the phenotype of lyn-deficient mice (Table 11).These mice have decreased numbers of mature peripheral B cells, greatly elevated serum IgM and IgA, and production of autoantibodies (Hibbs et al., 1995). I n uitro, Iyndeficient splenic B cells are hyperresponsive to BCR stimulation (Nishizumi et al., 1995; Wang et al., 1996; Chan et al., 1997). This pattern suggests a role for 1yn in the negative regulation of B cell activation. This function could be performed by 1yn by phosphorylating inhibitory receptors such as CD22 or FcyRII (Malbec et al., 1998; Smith et al., 1998; Nishizumi et al., 1998; Cornall et al., 1998), although the severe phenotype observed in the absence of lyn relative to the CD22 or FcyRII deficiencies indicates that other inhibitory signals must be dependent on lyn function. The tyrosine phosphatase SHP-2 shares domain structure and considerable overall sequence identity (55%) with SHP-1, but its function in inhibitory signaling is not as clear as for SHP-1. Although SHP-1 expression is mostly limited to hematopoietic cells, SHP-2 is ubiquitously expressed. Early studies indicated that SHP-2, as well as its Drosophila homolog

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TABLE I1 KNOCKOUTMICE Viability Cellularity Lung (monocytesl neutrophils) Spleen Peripheral B cells Monocyteslneutrophils Peritoneal (B1 cells) Immune function Autoantibodies Serum IgM In vitro stimulation Anti-IgM IgE CSF/ILS FcyRII

SHIP-’(12 weeks)

SHIP-1-’(2 weeks)

(24 weeks)

1y”-/-

FcyRIIP (normal)

t t

t

n.d:

n.d.

T

t

Normal

n.d.

.1

t

Normal n.d. Normal

.1

t

n.d. n.d. n.d.

t t

t

Normal

n.d.

t t

t 1

t t

t t 1

t

Normal

t n.d.

1

t

n.d.

.1

md.. not determined.

Corkscrew (CSW), played a positive role in growth factor signaling (Tang et al., 1995). A targeted deletion of the SH2 domain of SHP-2 leads to an embryonic lethality at midgestation in homozygous mutant mice, and reduced hematopoietic activity in differentiated SHP-2-’- ES cells (Qu et al., 1997). These results suggest that SHP-2 function is not restricted to immune cells, and that it is essential for signaling in tissue development. In this context, SHP-2 could positively regulate kinases by dephosphorylating inhibitory tyrosine phosphorylation sites, as has been shown for SHP-1 and Src kinases (Somani et al., 1997). An inhibitory function of SHP-2 could also explain embryonic lethality, if an excessive signal from growth factor receptors due to the absence of the inhibitory molecule SHP-2 is detrimental for cell development. Recent studies on the inhibitory receptors SIRPa, CTLA-4, and PIR-B have shown that their inhibitory signals are at least partially dependent on SHP-2 function (Marengere et al., 1996; Kharitonenkov et al., 1997; Maeda et al., 199813). These results point to an inhibitory role for SHP-2, consistent with its association, together with SHP-1, with most of the ITIM sequences in immune receptors. VII. Conclusions

Inhibitory receptors were unknown until quite recently; since their discovery the complexities of their actions have begun to be appreciated. It

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is now understood that inhibitory receptors share ligand specificity with activating counterparts and work in concert to determine threshold levels for cellular responses. The rapidly expanding family of inhibitory receptors raises the intriguing question as to their function in regulating the immune response. To date, well-defined ligands and clear physiological functions have been elucidated for the Fc receptor system and the NK inhibitory system. With these two molecules as prototypes of the family, significant differences have been observed in their mechanism of conferring inhibitory signals. The outcome of these pathways is either to abrogate all calcium responses or to modulate calcium responses by blocking influx and thereby impeding sustained calcium responses. At present, the physiological significance of this fine regulation of calcium is not apparent. Future studies will need to determine the functional consequences of engaging these discrete pathways as well as the ligands involved.

ACKNOWLEDGMENTS The authors wish to acknowledge the support of the National Institutes of Health and the S.L.E. Foundation of New York. The contribution of Raphael Clynes and Toshi Takai, whose unpublished results have been discussed in this review, is greatly appreciated. We are grateful to the members of the laboratory for helpful discussions and critical comments.

REFERENCES Aagaard-Tillery, K. M., and Jelinek, D. F. (1996). Phosphatidylinositol 3-kinase activation in normal human B lymphocytes. 1.lmmunol. 156,4543-4554. Adachi, T., Flaswinkel, H., Yakura, H., Reth, M., and Tsubata, T. (1998).The B cell surface protein CD72 recruits the tyrosine phosphatase SHP-1 upon tyrosine phosphorylation. I. Immunol. 160,4662-4665. Alberola-Ila, J., Takaki, S., Kemer, J. D., and Perlmutter, R. M. (1997). Differential signaling by lymphocyte antigen receptors I . Annu. Rev. lmmunol. 15, 125-154. Amigorena, S., Bonnerot, C., Drake, J. R., Choquet, D., Hunziker, W., Guillet, J. G., Webster, P., Sautes, C., Mellman, I., and Fridman, W. H. (1992). Cytoplasmic domain heterogeneity and functions of IgG Fc receptors in B lymphocytes. Science 256, 18081812. Auger, K. R., Serunian, L. A., Soltoff, S. P., Libby, P., and Cantley, L. C. (1989). PDGFdependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell 57, 167-175. August, A,, Sadra, A., Dupont, B., and Hanafusa, H. (1997). Src-induced activation of inducible T cell kinase (ITK) requires phosphatidylinositol 3-kinase activity and the Pleckstrin homology domain of inducible T cell kinase. Proc. Natl. Acad. Sci. U.S.A. 94, 11227-11232. Azzoni, L., Kamoun, M., Salcedo, T. W., Kanakaraj, P., and Perussia, B. (1992). Stimulation of Fc gamma RIIIA results in phospholipase C-gamma 1 tyrosine phosphorylation and p561ck activation. J. Exp. Med. 176, 1745-1750. Backer, J. M., Myers, M. J., Shoelson, S. E., Chin, D. J., Sun, X. J., Miralpeix, M., Hu, P., Margolis, B., Skolnik, E. Y., Schlessinger, J., et al. (1992). Phosphatidylinositol3’-kinase is activated by association with IRS-1 during insulin stimulation. EMBOJ. 11,3469-3479.

INHIBITION BY ITIM-CONTAINING RECEPTORS

167

Biassoni, R., Cantoni, C., Falco, M., Verdiani, S., Bottino, C., Vitale, M., Conte, R., Poggi, A., Moretta, A., and Moretta, L. (1996). The human leukocyte antigen (HLA)-C-specific “activatory”or “inhibitory” natural killer cell receptors display highly homologous extracellular domains but differ in their transmembrane and intracytoplasmic portions. J . Exp. Med. 183,645-650. Bijsterbosch, M. K., Meade, C. J., Turner, G. A,, and Klaus, G. G. (1985). B lymphocyte receptors and polyphosphoinositide degradation. Cell 41, 999-1006. Binstadt, B. A., Brumbaugh, K. M., Dick, C. J., Scharenberg, A. M., Williams, B. L., Colonna, M., Lanier, L. L., Kinet, J. P., Abraham, R. T., and Leibson, P. J. (1996). Sequential involvement of Lck and SHP-1 with MHC-recognizing receptors on NK cells inhibits FcR-initiated tyrosine kinase activation. Immunity 5, 629-638. Blery, M., Delon, J., Trautmann, A., Cambiaggi, A., Olcese, L., Biassoni, R., Moretta, L., Chavrier, P., Moretta, A., Daeron, M., and Vivier, E. (1997). Reconstituted killer cell inhibitory receptors for major histocompatibility complex Class I molecules control mast cell activation induced via immunoreceptor tyrosine-based activation motifs. J. Biol. Chem. 272,8989-8996. Blery, M., Kubagawa, H., Chen, C. C., Vely, F., Cooper, M. D., and Vivier, E. (1998). The paired Ig-like receptor PIR-B is an inhibitory receptor that recruits the protein-tyrosine phosphatase SHP-1. Proc. Nut. Acad. Sci. U.S.A. 95, 2446-2451. Bolland, S., Pearse, R. N., Kurosaki, T., and Ravetch, J. V. (1998). SHIP modulates immune receptor responses by regulating membrane association of Btk. Immunity 8, 509-516. Bonnerot, C., and Daeron, M. (1994). Biological activities of murine low-affinityFc receptors for IgG. lnimunomethods 4, 41-47. Brooks, A. G., Posch, P. E., Scorzelh, C. J., Borrego, F., and Coligan, J. E. (1997). NKG2A complexed with CD94 defines a novel inhibitory natural killer cell receptor. J. Exp. Med. 185, 795-800. Brunet, J. F., Denizot, F., Luciani, M. F., Row-Dosseto, M., Suzan, M., Mattei, M. G., and Golstein, P. (1987). A new member of the immunoglobulin superfamily-CTLA-4. Nature 328, 267-270. Burshtyn, D. N., Scharenberg, A. M., Wagtmann, N., Rajagopalan, S., Berrada, K., Yi, T., Kinet, J. P., and Long, E. 0. (1996). Recruitment of tyrosine phosphatase HCP by the killer cell inhibitor receptor. Immunity 4, 77-85. Burshtyn, D. N., Yang, W., Yi, T., and Long, E. 0. (1997). A novel phosphotyrosine motif with a critical amino acid at position -2 for the SH2 domain-mediated activation of the tyrosine phosphatase SHP-1. J. Bid. Chem. 272, 13066-13072. Campbell, K. S., Dessing, M., Lopezbotet, M., Cella, M., and Colonna, M. (1996).Tyrosine phosphorylation of a human killer inhibitory receptor recruits protein tyrosine phosphatase 1C. J. Exp. Med. 184, 93-100. Carpenter, C. L., and Cantley, L. C. (1996). Phosphoinositide kinases. Curr. Opin. Cell Bid. 8, 153-158. Carretero, M., Cantoni, C., Bellon, T., Bottino, C., Biassoni, R., Rodriguez, A., Perez-Villar, J. J., Moretta, L., Moretta, A,, and Lopez-Botet, M. (1997). The CD94 and NKG2-A Ctype lectins covalently assemble to form a natural killer cell inhibitory receptor for HLA class I molecules. Eur. J. Immunol. 27, 563-567. Carretero, M., Palmieri, G., Llano, M., TulLio, V., Santoni, A,, Geraghty, D. E., and Lopezbotet, M. (1998). Specific engagement of the CD94lNKG2A killer inhibitory receptor by the HLA-E Class IB molecule induces SHP-1 phosphatase recruitment to tyrosinephosphorylated NKG-A-Evidence for receptor function in heterologous tranfectants. Eur. J. Immunol. 28, 1280-1291.

168

SILVIA BOLLAND AND JEFFREY V. RAVETCH

Castells, M. C. (1994). Surface makers for mast cell subtypes: Low &nity IgG receptors and gp49 family. Allergie Immunol. 26, 127-131. Castells, M. C., Wu, X.,Arm, J. P., Austen, K. F., and Katz, H. R. (1994). Cloning of the gp49B gene of the immunoglobulin superfamily and demonstration that one of its two products is an early-expressed mast cell surface protein originally described as gp49. 1.Biol. Chem. 269, 8393-8401. Chacko, G. W., Tridandapani, S., Damen, J. E., Liu, L., Krystd, G., and Coggeshall, K. M. (1996). Negative signaling in B lymphocytes induces tyrosine phosphorylation of the 145-kDa inositol polyphosphate 5-phosphatase, SHIP. I. Immunol. 157,2234-2238. Chan, P. L., and Sinclair, N. R. S. C. (1971). Regulation of the immune response: V. An analysis of the function of the Fc portion of antibody in suppression of an immune response with respect to interaction with components of the lymphoid system. Immunology 21, 967-987. Chan, V. W. F., Meng, F. Y.,Soriano, P., DeFranco, A. L., and Lowell, C. A. (1997). Characterization of the B lymphocyte populations in lyn-deficient mice and the role of lyn in signal initiation and down-regulation. Immunity 7, 69-81. Chang, C., Rodriguez, A,, Carretero, M., Lopez-Botet, M., Phillips, J. H., and Lanier, L. L. (1995).Molecular characterization of human CD94: A type I1 membrane glycoprotein related to the C-type lectin superfamily. Eur. J. Immunol. 25, 2433-2437. Choquet, D., Partiseti, M., Amigorena, S., Bonnerot, C., Fridman, W. H., and Kom, H. (1993). Cross-linking of IgG receptors inhibits membrane immunoglobulin-stimulated calcium influx in B lymphocytes. J. Cell Biol. 121, 355-363. Clynes, R., Maizes, J., Guinamard, R., and Ravetch, J. V. (1998). Modulation of immune complex induced inflammation by the coordinate expression of activation and inhibitory receptors. J. Exp. Med., in press. Colonna, M., and Samaridis, J. (1995). Cloning of immunoglobulin-superfamily members associated with HLA-C and HLA-B recognition by human natural killer cells. Science 268,405-408. Cornall, R. J., Cyster, J. G., Hibbs, M. L., Dunn, A. R. R., Otipoby, K. L., Clark, E. A., and Goodnow, C. C. (1998). Polygenic autoimmune traits: Lyn, CD22 and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection. Immunity 8, 497-508. Coughlin, S. R., Escobedo, J. A,, and Williams, L. T. (1989). Role of phosphatidylinositol lanase in PDGF receptor signal transduction. Science 243, 1191-1194. Crowley, M. T., Harmer, S. L., and DeFranco, A. L. (1996). Activation-induced association of a 145-kDa tyrosine-phosphorylated protein with Shc and Syk in B lymphocytes and macrophages. J. Biol. Chem. 271, 1145-1152. Cyster, J. G., and Goodnow, C. C. (1995). Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection. Immunity 2, 13-24. Daeron, M. (1997). Fc receptor biology. Annu. Rev. Immunol. 15, 203-234. Daeron, M., Latour, S., Malbec, O., Espinosa, E., Pina, P., Pasmans, S., and Fridman, W. H. (1995a). The same tyrosine-based inhibition motif, in the intracytoplasmic domain of Fc gamma RIIB, regulates negatively BCR-, TCR-, and FcR-dependent cell activation. Immunity 3, 635-646. Daeron, M., Malbec, 0.. Latour, S., Arock, M., and Fridman, W. H. (1995b). Regulation of high-affinity IgE receptor-mediated mast cell activation by murine low-affinity IgG receptors. 1.Clin. Invest. 95, 577-585. D’Ambrosio, D., Hippen, K. L., Minskoff, S. A., Mellman, I., Pani, G., Siminovitch, K. A,, and Cambier, J. C. (1995). Recruitment and activation of PTPlC in negative regulation of antigen receptor signaling by Fc gamma RIIB1. Science 268, 293-297.

INHIBITION BY ITIM-CONTAINING RECEPTORS

169

Damen, J. E., Liu, L., Rosten, P., Humphries, R. K., Jefferson, A. B., Majerus, P. W., and Krystal, G. (1996). The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-trisphosphate 5phosphatase. Proc. Natl. Acad. Sci. U.S.A. 93, 1689-1693. D'Andrea, A., Chang, C., Franz-Bacon, K., McClanahan, T., Phillips, J. H., and Lanier, L. L. (1995). Molecular cloning of NKB1. A natural killer cell receptor for HLA-B allotypes.J. lmmunol. 155, 2306-2310. de Weers, M., Mensink, R. G., Kraakman, M. E., Schuurman, R. K., and Hendriks, R. W. (1994). Mutation analysis of the Bruton's tyrosine kinase gene in X-linked agammaglobulinemia: Identification of a mutation which affects the same codon as is alteredin immunodeficient xid mice. Hurnan Mol. Genet. 3, 161-166. Dolmetsch, R. E., Lewis, R. S., Goodnow, C. C., and Healy, J. I. (1997). Differential activation of transcription factors induced by Ca2+response amplitude and duration. Nature 386, 855-858. Doody, G. M., Justement, L. B., Delibrias, C. C., Matthews, R. J., Lin, J., Thomas, M. L., and Fearon, D. T. (1995). A role in B cell activation for CD22 and the protein tyrosine phosphatase SHP. Science 269, 242-244. Fluckiger, A. C., Li, Z., Kato, R. M., Wahl, M. I., Ochs, H. D., Longnecker, R., Kinet, J. P., Witte, 0. N., Scharenberg, A. M., and Rawlings, D. J. (1998). Btk/Tec kinases regulate sustained increases in intracellular Ca" following B-cell receptor activation. EMBO 1. 17, 1973-1985. Fong, D. C., Malbec, O., Arock, M., Cambier, J. C., Fridman, W. H., and Daeron, M. (1996). Selective in uivo recruitment of the phosphatidylinositol phosphatase SHIP by phosphorylated Fc-gamma-RIIB during negative regulation of IgE-dependent mouse mast cell activation. lmmunol. Lett. 54, 83-91. Fry, A. M., Lanier, L. L., and Weiss, A. (1996). Phosphotyrosines in the killer cell inhibitory receptor motif of NKBl are required for negative signaling and for association with protein tyrosine phosphatase 1C. J. Exp. Med. 184, 295-300. Gold, M. R., and Aebersold, R. (1994). Both phosphatidylinositol3-kinase and phosphatidylinositol4-kinase products are increased by antigen receptor signalingin B cells.]. lmmunol. 152,42-50. Gupta, N., Scharenberg, A. M., Burshtyn, D. N., Wagtmann, N., Lioubin, M. N., Rohrschneider, L. R., Kinet, J. P., and Long, E. 0. (1997). Negative signaling pathways of the killer cell inhibitory receptor and Fc-gamma-RIIB 1require distinct phosphatases. 1.Exp. Med. 186,473-478. Healy, J. I., and Goodnow, C. C. (1998). Positive versus negative signaling by lymphocyte antigen receptors. Annu. Rev. lmmunol. 16, 645-670. Helgason, C. D., Damen, J. E., Rosten, P., Grewal, R., Sorensen, P., Chappel, S. M., Borowski, A., Jirik, F., Krystal, G., and Humphries, R. K. (1998). Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology, and a shortened life span. Genes Deu. 12, 1610-1620. Hibbs, M. L., Tarlinton, D. M., Armes, J., Grail, D., Hodgson, G., Maglitto, R., Stacker, S. A., and Dunn, A. R. R. (1995). Multiple defects in the immune system of lyn-deficient mice, culminating in autoimmune disease. Cell 83, 301-311. Hippen, K. L., Buhl, A. M., Dambrosio, D., Nakamura, K., Persin, C., and Cambier, J. C. (1997). Fc-gamma-RIIB 1 inhibition of BCR-mediated phosphoinositide gydrolysis and Ca2+mobilization is integrated by CD19 dephosphorylation. Immunity 7 , 49-58. Hogquist, K. A,, Jameson, S. C., Heath, W. R., Howard, J. L., Bevan, M. J., and Carbone, F. R. (1994).T cell receptor antagonist peptides induce positive selection. Cell 76,17-27.

170

SILVIA BOLLAND AND JEFFREY V. RAVETCH

Houchins, J. P., Lanier, L. L., Niemi, E. C., Phillips, J. H., and Ryan, J. C. (1997). Natural killer cell cytolytic activity is inhibited by NKG2-A and activated by NKG2-C.J. Immunol. 158,3603-3609. Hunter, M. G., and Avalos, B. R. (1998). Phosphatidylinositol3'-kinaseand SH2-containing inositol phosphatase (SHIP) are recruited by distinct positive and negative growthregulatory domains in the granulocyte colony-stimulating factor receptor. J. Immunol. 160,4979-4987. Hyvonen, M., and Saraste, M. (1997). Structure of the PH domain and Btk motif from Bruton's tyrosine kinase-Molecular explanations for X-linked agammaglobulinaemia. EMBO J. 16,3396-3404. Jefferson, A. B., and Majerus, P. W. (1995). Properties of type I1 inositol polyphosphate 5-phosphatase. J. Biol. Chem. 270,9370-9377. Karlhofer, F. M., Ribaudo, R. K., and Yokoyama, W. M. (1992). MHC class I dloantigen specificity of Ly-49+ IL-%activated natural killer cells. Nature 358, 66-70. Karre, K., Ljunggren, H. G., Piontek, G., and Kiessling, R. (1986). Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319, 675-678. Katz, H. R., and Lobell, R. B. (1995). Expression and function of Fc gamma R in mouse mast cells. Int. Arch. Allergy Immunol. 107, 76-78. Kaufman, D. S., Schoon, R. A., Robertson, M. J., and Leibson, P. J. (1995). Inhibition of selective signaling events in natural killer cells recognizing major histocompatibility complex class I. Proc. Nat. Acad. Sci. U.S.A. 92,6484-6488. Kavanaugh,W. M., Turck, C. W., and Williams, L. T. (1995).PTB domain binding to signaling proteins through a sequence motif containing phosphotyrosine. Science 268,1177-1 179. Kavanaugh, W. M., Pot, D. A,, Chin, S. M., Deuterreinhard, M., Jefferson, A. B., Noms, F. A, Masiarz, F. R., Cousens, L. S., Majerus, P. W., and Williams, L. T. (1996). Multiple forms of an inositol polyphosphatase 5-phosphatase form signaling complexes with Shc and Grb2. C u m Biol. 6, 438-445. Kharitonenkov, A., Chen, Z., Sures, I., Wang, H., Schilling, J., and Ullrich, A. (1997). A family of proteins that inhibit signalling through tyrosine kinase receptors. Nature 386, 181-186. Kimura, T., Sakamoto, H., Appella, E., and Siraganian, R. P. (1997a). The negative signaling molecule SH2 domain-containing inositol- polyphosphate 5-phosphatase (SHIP) binds to the tyrosine- phosphorylated beta subunit of the high affinity IgE receptor. J . Biol. Chem. 272,13991 -13996. Kimura, T., Zhang, J., Sagawa, K., Sakaguchi, K., Appella, E., and Siraganian, R. P. (1997b). Syk-independent tyrosine phosphorylation and association of the protein tyrosine phosphatases SHP-1 and SHP-2 with the high affinity IgE receptor. J. Immunol. 159,4426-4434. Klingmuller, U., Lorenz, U., Cantley, L. C., Neel, B. G., and Lodish, H. F. (1995). Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 80, 729-738. Kojima, T., Fukuda, M., Watanabe, Y., Hamazato, F., and Mikoshiba, K. (1997). Characterization of the pleckstrin homology domain of Btk as an inositol polyphosphate andphosphoinositide binding domain. Bwchem. Biophys. Res. Commun. 236, 333-339. Konkozlowski, M., Pani, G., Pawson, T., and Siminovitch, K. A. (1996).The tyrosinephosphatase PTPlC associates with vav, grb2, and msosl in hematopoietic cells. J. Biol. Chem. 271,3856-3862. Kozlowski, M., Larose, L., Lee, F., Le,D. M., Rottapel, R., and Siminovitch, K. A. (1998). SHP-1 binds and negatively modulates the c-Kit receptor by interaction with tyrosine 569 in the c-Kit juxtamembrane domain. Mol. Cell. Biol. 18,2089-2099.

INHIBITION BY ITIM-CONTAINING RECEPTORS

171

Kubagawa, H., Burrows, P. D., and Cooper, M. D. (1997).A novel pair of immunoglobulinlike receptors expressed by B cells and rnyeloid cells [see comments]. Proc. Nutl. Acnd. Sci. U.S.A. 94, 5261-5266. Kubagawa, H., Chen, C. C., Ho, L. H., Gartland, L., Shimada, T., Mashburn, C., Ravetch, J. V., and Cooper, M. D. (1998). Biochemical nature and cellular distribution of the Paired Immunoglobulin-Likereceptors, PIR-A and PIR-B. J. Exp. Med., in press. Kuroiwa, A., Yamashita, Y., Inui, M., Yuasa, T., Ono, M., Nagabukuro, A., Matsuda, Y., and Takai, T. (1998). Association of tyrosine phosphatases SHP-1 and SHP-2, inositol5phosphatase SHIP with gp49B1, and chromosomal assignment of the gene.]. Biol. Chem. 273, 1070-1074. Kurosaki, T. (1997). Molecular mechanisms in B cell antigen receptor signaling. Cum. Opin. Immunol. 9,309-318. Kurosaki, T., Gander, I., and Ravetch, J. V. (1991).A subunit common to an IgG Fc receptor and the T-cell receptor mediates assembly through different interactions. Proc. Natl. Acad. Sci. U.S.A. 88, 3837-3841. Lamkin, T. D., Walk, S. F., Liu, L., Damen, J. E., Krystal, G., and Ravichandran, K. S. (1997). Shc interaction with Src homology 2 domain containing inositol phosphatase (SHIP) in uiuo requires the Shc-phosphotyrosine binding domain and two specific phosphotyrosines on SHIP. J. Biol. Chem. 272, 10396-10401. Langhans-Rajasekaran, S. A,, Wan, Y., and Huang, X. Y. (1995). Activation of Tsk and Btk tyrosine kinases by G protein beta gamma subunits. Proc. Nut]. Acud. Sci. U.S.A. 92,8601-8605. Lanier, L. L. (1997). Natural killer ceIl receptors and MHC class I interactions. Cum. Opin. Inmwnol. 9, 126-131. Lanier, L. L. (1998a). Follow the leader: NK cell receptors for classical and nonclassical MHC class I. Cell 92, 705-707. Lanier, L. L. (1998b). NK cell receptors. Annu. Reu. Immunol. 16, 359-393. Lanier, L. L., Corliss, B. C., Wu, J., Leong, C., and Phillips, J. H. (1998a). Immunoreceptor DAPl2 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391, 703-707. Lanier, L. L., Corliss, B. C., Wu, J., and Phillips, J. H. (1998b). Association of DAP12 with activating CD9mKG2C NK cell receptors. Immunity 8, 693-701. Ledrean, E., Vely, F., Olcese, L., Cambiaggi, A,, Guia, S., Krystal, G., Gervois, Moretta, A., Jotereau, F., and Vivier, E. (1998). Inhibition of antigen-induced T cell response and antibody-induced NK cell cytotoxicity by NKG2A: Association of NKG2A with SHP-1 and SHP-2 protein-tyrosine phosphatases. Eur. 1.Immunol. 28, 264-276. Lemmon, M. A., Ferguson, K. M., and Schlessinger, J. (1996). PH domains: Diverse sequences with a common fold recruit signaling molecules to the cell surface. Cell 85, 621-624. Li, T., Tsukada, S., Satterthwaite, A,, Havlik, M. H., Park, H., Takatsu, K., and Witte, 0. N. (1995). Activation of Bmton’s tyrosine kinase (BTK) by a point mutation in its pleckstrin homology (PH) domain. Immunity 2,451-460. Lioubin, M. N., Algate, P. A,, Tsai, S., Carlberg, K., Aebersold, A., Rohrschneider, and LR. (1996). pl50Ship, a signal transduction molecule with inositol polyphosphate-5phosphatase activity. Genes Deu. 10, 1084-1095. Liu, L., Damen, J. E., Cutler, R. L., and Krystal, G. (1994). Multiple cytokines stimulate the binding of a common 145-kilodalton protein to Shc at the Grb2 recognition site of Shc. Mol. Cell. Biol. 14, 6926-6935. Liu, L., Jefferson, A. B., Zhang, X., Norris, F. A,, Majerus, P. W., and Krystal, G. (1996). A novel phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase associates with the interleukin-3 receptor. /. Biol. Chem. 271, 29729-29733.

172

SILVIA BOLLAND AND JEFFREY V. RAVETCH

Liu, L., Damen, J. E., Ware, M. D., and Krystal, G. (1997). Interleukin-3 induces the association of the inositol 5-phosphatase SHIP with SHP2. I. Biol. Chem. 272, 10998-

11001. Liu, Q., Oliveira-Dos-Santos, A. J., Mariathasan, S., Bouchard, D., Jones, J., Sarao, R., Kozieradzki, I., Ohashi, P. S., Penninger, J. M., and Dumont, D. J. (1998). The inositol polyphosphate 5-phosphatase Ship is a crucial negative regulator of BCR signaling. J. Exp. Med. 188, 1333-1342. Lopez, F., Esteve, J. P., Buscail, L., Delesque, N., Saint-Laurent, N., Theveniau, Nahmias, C., Vaysse, N., and Susini, C. (1997). The tyrosine phosphatase SHP-1 associates with the sst2 somatostatin receptor and is an essential component of sst2-mediated inhibitory growth signaling. J. Biol. Chem. 272, 24448-24454. Lorenz, U., Bergemann, A. D., Steinberg, H. N., Flanagan, J. G., Li, X. T., G&, S. J., and Nee], B. G. (1996).Genetic analysisreveals cell type-specificregulation of receptor tyrosine kinase c-kit by the protein tyrosine phosphatase SHP1. J. Exp. Med. 184, 1111-1126. Luckhoff, A., and Clapham, D. E. (1992). Inositol 1,3,4,5-tetrakisphosphateactivates an endothelial Ca(2+)-permeable channel. Nature 355, 356-358. Maeda, A., Kurosaki, M., and Kurosaki, T. (1998a). Paired immunoglobulin-like receptor (P1R)-A is involved in activating mast cells through its association with Fc receptor y chain. J . Exp. Med. 188,991-995. Maeda, A,, Kurosaki, M., Ono, M., Takai, T., and Kurosaki, T. (199813). Requirement of SH2-containingprotein tyrosine phosphatases SHP-1 and SHP-2 for paired immunoglobulin-like receptor B (PIR-B)-mediated inhibitory signal. J. Exp. Med. 187, 1355-1360. Malbec, O., Fong, D. C., Turner, M., Tybulewicz, V. L., Cambier, J. C., Fridman, W. H., and Daeron, M. (1998). Fc epsilon receptor I-associated lyn-dependent phosphorylation of Fc gamma receptor IIB during negative regulation of mast cell activation.J. Immunol. 160, 1647-1658. Marengere, L. E., Waterhouse, P., Duncan, G. S., Mittrucker, H. W., Feng, G. S., Mak, and TW. (1996). Regulation of T cell receptor signaling by tyrosine phosphatase SW association with CTLA-4. Science 272, 1170-1173. Mason, L. H., Gosselin, P., Anderson, S. K., Fogler, W. E., Ortaldo, J. R., and McVicar, D. W. (1997). Differential tyrosine phosphorylation of inhibitory versus activating Ly-49 receptor proteins and their recruitment of SHP-1 phosphatase. J. Immunol. 159,41874196. Matsushita, M., Yamadori, T., Kato, S., Takemoto, Y., Inazawa, J., Baba, Y., Hashimoto, S., Sekine, S., Arai, S., Kunikata, T., Kurimoto, M., Kishimoto, T., and Tsukada, S. (1998). Identification and characterization of a novel SH3-domain binding protein, Sab, which preferentially associates with Bruton's tyrosine kinase (BtK). Biochem. Biophys. Res. Commun. 245,337-343. Meyaard, L., Adema, G. J., Chang, C., Woollatt, E., Sutherland, G. R., Lanier, L. L., and Phillips, J. H. (1997). LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes. Immunity 7 , 283-290. Moretta, A., Bottino, C., Pende, D., Tripodi, G., Tambussi, G., Vide, O., Orengo, A., Barbaresi, M., Merli, A., and Ciccone, E. (1990). Identification of four subsets of human CD3-CD16' natural killer (NK) cells by the expression of clonally distributed functional surface molecules: Correlation between subset assignment of NK clones and ability to mediate specific alloantigen recognition. J. Exp. Med. 172, 1589-1598. Moretta, A., Vitde, M., Bottino, C., Orengo, A. M., Morelli, L., Augugliaro, R., Barbaresi, M., Ciccone, E., and Moretta, L. (1993). P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells.

INHIBITION BY ITIM-CONTAINING RECEPTORS

173

Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities.J . Erp. Med. 178, 597-604. Moretta, A., Biassoni, R., Bottino, C., Pende, D., Vitale, M., Poggi, A., Mingari, M. C., and Moretta, L. (1997). Major histocompatibility complex class I-specific receptors on human natural killer and T lymphocytes. ImmunoE. Rev. 155, 105-117. Muta, T., Kurosaki, T., Misulovh, Z., Sanchez, M., Nussennveig, M. C., and Ravetch, J. V. (1994). A 13-amino-acid motif in the cytoplasmic domain of Fc gamma RIIB modulates B-cell receptor signalling. Nature 368, 70-73. Nadler, M. J. S., Chen, B. B., Anderson, J. S.,Wortis, H. H., and Neel, B. G. (1997). Proteintyrosine phosphatase SHP-1 is dispensable for Fc-gamma-RIIB-mediated inhibition of B cell antigen receptor activation. J. Biol. Chem. 272, 20038-20043. Nakamura, M. C., Niemi, E. C., Fisher, M. J., Shultz, L. D., Seaman, W. E., and Ryan, J. C. (1997). Mouse Ly-49A interrupts early signalingevents in natural killer cell cytotoxicity and functionally associates with the SHP-I tyrosine phosphatase. J. Erp. Med. 185, 673-684. Nakanishi, H., Brewer, K. A,, and Exton, J. H. (1993). Activation of the zeta isozyme of protein kinase C by phosphatidyliriosito13,4,5-trisphosphate.1.Biol. Chem. 268, 13-16. Nakayama, E., Von, H. I., and Parnes, J. R. (1989).Sequence of the Lyb-2 B-cell differentiation antigen defines a gene superfamily of receptors with inverted membrane orientation. Proc. Natl. Acad. Sci. U.S.A. 86, 1352-1356. Nishizumi, H., Taniuchi, I., Yamanashi, Y., Kitamura, D., Ilic, D., Mori, S., Watanabe, T., and Yamamoto, T. (1995). Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient mice. Immunity 3,549-560. Nishizumi, H., Horikawa, I., Mlinaric-Rascan,I., and Yamamoto, T. (1998).A double-edged kinase lyn: A positive and negative regulator for antigen receptor-mediated signals. J. Erp. Med. 187, 1343-1348. Nossd, G. J. (1994). Negative selection of lymphocytes. Cell 76, 229-239. Olcese, L., Lang, P., Vely, F., Cambiaggi, A,, Marguet, D., Blery, M., Hippen, KL, Biassoni, R., Moretta, A., Moretto, L., Cambier, J. C., and Vivier, E. (1996). Human and mouse killer-cell inhibitory receptors recruit PTPlC and PTPlD protein tyrosine phosphatases. J. Immuml. 156,4531-4534. Olcese, L., Cambiaggi, A,, Semenzato, G., Bottino, C., Moretta, A,, and Vivier, E. (1997). Human killer cell activatory receptors for MHC Class I molecules are included in a multimeric complex expressed by natural killer cells. J. Immunol. 158, 5083-5086. Ono, M., Bolland, S., Tempst, P., and Ravetch, J. V. (1996). RoIe ofthe inositol phosphatase SHIP in negative regulation of the immune system by the receptor Fc-gamma-RIIB. Nature 383, 263-266. Ono, M., Okada, H., Bolland, S., Yanagi, S., Kurosaki, T., and Ravetch, J. V. (1997). Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. Cell 90,293-301. Orourke, L., Tooze, R., and Fearon, D. T. (1997). Co-receptors of B lymphocytes. Curr. Opin. Immunol. 9, 324-329. Osborne, M. A,, Zenner, G., Lubinus, M., Zhang, X., Songyang, Z., Cantley, L. C., Majerus, P., Bum, P., and Kochan, J. P. (1996).The inositol5'-phosphatase SHIP binds to immunoreceptor signaling motifs and responds to high affinity IgE receptor aggregation. J. Biol. Chem. 271,29271-29278. Pani, G., Kozlowski, M., Cambier, J. C., Mills, G. B., and Siminovitch, K. A. (1995). Identification of the tyrosine phosphatase PTPlC as a B cell antigen receptor-associated protein involved in the regulation of B cell signaling. J. Exp. Med. 181, 2077-2084. Pani, G., Fischer, K. D., Mlinaricrascan, I., and Siminovitch, K. A. (1996). Signaling capacity of the T cell antigen receptor is negatively regulated by the PTPlC tyrosine phosphatase. I. Exp. Med. 184, 839-852.

174

SILVIA BOLLAND AND JEFFREY V. RAVETCH

Paulson, R. F., Vesely, S., Siminovitch, K. A., and Bernstein, A. (1996). Signalling by the wkit receptor tyrosine kinase is negatively regulated in vivo by the protein tyrosine phosphatase SHP1. Nature Genet. 13,309-315. Pei, D., Lorenz, U., Klingmuller, U., Neel, B. G., and Walsh, C. T. (1994). Intramolecular regulation of protein tyrosine phosphatase SH- PTP1: A new function for Src homology 2 domains. Biochemistry 33, 15483-15493. Pei, D., Wang, J., and Walsh, C. T. (1996). Differential functions of the two Src homology 2 domains in protein tyrosine phosphatase SH-FTP1. Proc. Nutl. Acud. Sci. U.S.A. 93, 1141-1145. Phillips, N. E., and Parker, D. C. (1983). Fc-dependent inhibition of mouse B cell activation by whole anti-mu antibodies. J. lmmunol. 130, 602-606. Phillips, N. E., and Parker, D. C. (1984). Cross-linkingof B lymphocyte Fc gamma receptors and membrane immunoglobulin inhibits anti-immunoglobulin-induced blastogenesis. J. lmmunol. 132,627-632. Plas, D. R., Johnson, R., Pingel, J. T., Matthews, R. J., Dalton, M., Roy, G., Chan, A. C., and Thomas, M. L. (1996). Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling. Science 272, 1173-1176. Pleiman, C. M., Hertz, W. M., and Cambier, J. C. (1994).Activation of phosphatidylinositol3’ kinase by Src-family kinase SH3 binding to the p85 subunit. Science 263,1609-1612. Pradhan, M., and Coggeshall, K. M. (1997). Activation-induced bi-dentate interaction of SHIP and Shc in B lymphocytes C. J. Cell. Biochem. 67,32-42. Qu, C. K., Shi, Z. Q., Shen, R., Tsai, F. Y., Orkin, S. H., and Feng, G. S. (1997). A deletion mutation in the SH2-N domain of Shp-2 severely suppresses hematopoietic cell development. Mol. Cell. Biol. 17, 5499-5507. Raab, M., and Rudd, C. E. (1996). Hematopoietic cell phosphatase (HCP) regulates p561ck phosphorylation and ZAP-70 binding to T cell receptor zeta chain. Biochem. Biophys. Res. Commun. 222,50-57. Rajewsky, K. (1996). Clonal selection and learning in the antibody system. Nature 381, 751-758. Rameh, L. E., Arvidsson Ak, Carraway, K. L. 3., Couvillon, A. D., Rathbun, G., Crompton, A., VanRenterghem, B., Czech, M. P., Ravichandran, K. S., Burakoff, S. J., Wang, D. S., Chen, C. S., and Cantley, L. C. (1997). A comparative analysis of the phosphoinositide binding specificity of pleckstrin homology domains. J. Biol. Chem. 272, 22059-22066. Ravetch, J. V. (1994). Fc receptors: Rubor redw. Cell 78, 553-560. Ravetch, J. V. (1997). Fc receptors. Cuw. Opin. lmmunol. 9, 121-125. Ravetch, J. V., and Kinet, J. P. (1991). Fc receptors. Annu. Reu. lmmunol. 9,457-492. Salim, K., Bottomley, M. J., Querfurth, E., Zvelebil, M. J., Gout, I., Scaife, R., Margolis, R. L., Gigg, R., Smith, C. I., Driscoll, P. C., Waterfield, M. D., and Panayotou, G. (1996). Distinct specificity in the recognition of phosphoinositides by the pleckstrin homology domains of dynamin and Bruton’s tyrosine kinase. EMBO J. 15, 6241-6250. Samaridis, J., and Colonna, M. (1997). Cloning of novel immunoglobulin superfamily receptors expressed on human myeloid and lymphoid cells: Structural evidence for new stimulatory and inhibitory pathways. Eur. J. lmmunol. 27, 660-665. Scharenberg, A. M., El-Hillal, O., Fruman, D. A., Beitz, L. O., Li, Z., Lin, S., Gout, Candey, L. C., Rawlings, D. J., and Kinet, J. P. (1998). Phosphatidylinositol-3,4,5-trisphosphate (PtdIns-3,4,5-P3)/Tec base-dependent calcium signaling pathway: A target for SHIPmediated inhibitory signals. EMBO J. 17, 1961-1972. Sebzda, E., Wallace, V. A., Mayer, J., Yeung, R. S., Mak, T. W., and Ohashi, P. S. (1994). Positive and negative thymocyte selection induced by different concentrations of a single peptide. Science 263, 1615-1618.

INHIBITION BY ITIM-CONTAINING RECEPTORS

175

Shultz, L. D., Schweitzer, P. A., Rajan, T. V., Yi, T., Ihle, J. N., Matthews, R. J., Thomas, M. L., and Beier, D. R. (1993). Mutations at the murine motheaten locus are within the heinatopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell 73, 1445-1454. Sihciano,J. D., Morrow, T. A., and Desiderio, S. (1992). Itk, a T-cell-specifictyrosine kinase gene inducible by interlleukin 2. Proc. Natl. Acnd. Sci. U.S.A. 89, 11194-11198. Smit, L., van der Horst, G., and Borst, J. (1996). Sos, Vav, and C3G participate in B cell receptor-induced signaling pathways and differentially associate with Shc-Grb2, Crk, and Crk-L adaptors. J. Biol. Chem. 271, 8564-8569. Smith, C . I., Islam, K. B., Vorechovsky, I., Olerup, 0..Wallin, E., Rabbani, H., Baskin, B., and Hammarstrom, L. (1994).X-Linked agammaglobulineniiaand other immunoglobulin deficiencies. Irnmunol. Reo. 138, 159-183. Smith, K. C., Tarlinton, D. M., Doody, G. M., Hibbs, M. L., and Fearon, D. T. (1998). Inhibition of the B cell by CD22-A requirement for lyn. 1.Exp. Med. 187, 807-811. Smith, K. M., Wu, J., Bakker, A. H., Phillips, J. H., and Lanier, L. L. (1998). Ly-49H associate with mouse DAPl2 and form activating receptors. J. Zmmunol. 161, 7-10. Somani, A. K., Bignon, J. S., Mills, G. B., Siminovitch, K. A,, and Branch, D. R. (1997). Src kinase activity is regulated by the SHP-1 protein-tyrosine phosphatase. J Biol. Chem. 272,21113-21119. Sugawara, H., Kurosaki, M., Takata, M., and Kurosaki, T. (1997). Genetic evidence for involvement of type 1, type 2, and type 3 inositol 1,4,5-trisphosphate receptors in signal transduction through the B-cell antigen receptor. EMBO J 16, 3078-3088. Takai, T., Ono, M., Hihda, M., Ohmori, H., and Ravetch, J. V. (1996).Augmented humoral and anaphylactic responses in Fc gamma RII-deficient mice. Nature 379, 346-349. Takata, M., and Kurosaki, T. (1996). A role for Brutons tyrosine kinase in B cell antigen recepor-mediated activation of phospholipase C-gamma-2.1. Exp. Med. 184, 31-40. Takata, M., Sabe, H., Hata, A., Inazu, T., Homma, Y., Nukada, T., Tamamura, H., and Kurosaki, T. (1994). Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca” mobilization through distinct pathways. EMBO J. 13, 1341-1349. Takata, M., Homma, Y., and Kurosaki, T. (1995). Requirement of phospholipase C-gamma2 activation in surface immunoglobulin M-induced B cell apoptosis. 1. Exp. Med. 182, 907-914. Tang, T. L., Freeman, R. M., Jr., OReilIy, A. M., Neel, B. G., and Sokol, S. Y. (1995). The SHZ-containing protein-tyrosine phosphatase SH-PTP2 is required upstream of MAP kinase for early Xenopus development. Cell 80, 473-483. Thompson, J. A,, Grunert, F., and Zimmermann, W. (1991). Carcinoembryonic antigen gene family: Molecular biology and clinical perspectives. 1.Clin. Lab. And. 5, 344-366. Ting, A. T., Karnitz, L. M., Schoon, R. A,, Abraham, R. T., and Leibson, P. J. (1992). Fc gamma receptor activation induces the tyrosine phosphorylation of both phospholipase C (PLC)-gamma 1 and PLC-gamma 2 in natural killer cells.]. Exp. Med. 176,1751-1755. Toker, A., and Cantley, L. C. (1997). Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 387, 673-676. Toker, A,, Meyer, M., Reddy, K. K., Falck, J. R., Aneja, R., Aneja, S., Parra, A., Bums, D. J., Ballas, L. M., and Cantley, L. C. (1994). Activation of protein kinase C family members by the novel polyphosphoinositides PtdIns-3,4-P2 and PtdIns-3,4,5-P3, J. B i d . Chem. 269, 32358-32367. Traynor-Kaplan, A. E., Harris, A. E., Thompson, B. L., Taylor, P., and SMar, L. A. (1988). An inositol tetrakisphosphate-containing phospholipid in activated neutrophils. Nature 334, 353-356. Tsui, H. W., Siminovitch, K. A., de Souza, L., and Tsui, F. W. (1993). Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nature Genet. 4, 124-129.

176

SILVIA BOLLAND AND JEFFREY V. RAVETCH

Tuveson, D. A., Carter, R. H., Soltoff, S. P., and Fearon, D. T. (1993). CD19 of B cells as a surrogate kinase insert region to bind phosphatidylinositol 3-base. Science 260, 986-989. Ujike, A,, Ishikawa, Y., Ono, M., Yuasa, T., Yoshino, T., Fukumoto, M., Ravetch, J. V., and Takai, T. (1999). Modulation of IgE-mediated systemic anaphylaxis by low affinity Fc receptors for IgG. (in preparation) Van de Velde, H., van Hoegen, I., Luo, W., Parnes, J. R., and Thielemans, K. (1991).The B-cell surface protein CD72/Lyb-2 is the ligand for CD5. Nature 351, 662-665. Vely, F., and Vivier, E. (1997). Conservation of structural features reveals the existence of a large family of inhibitorycell surfacereceptors and noninhibitory/activatorycounterparts. 1.lmmunol. 159, 2075-2077. Vely, F., Olivero, S., Olcese, L., Moretta, A,, Damen, J. E., Liu, L., Krystal, G., Cambier, J. C., Daeron, M., and Vivier, E. (1997). Differential association of phosphatases with hematopoietic co-receptors bearing immunoreceptor tyrosine-based inhibition motifs. Eur. J. lmmunol. 27,1994-2000. Vivier, E., and Daeron, M. (1997).Immunoreceptortyrosine-basedinhibition motifs. lmmunol. Today 18,286-291. Wang, J. Y., Koizumi, T., and Watanabe, T. (1996). Altered antigen receptor signaling and impaired Fas-mediated apoptosis of B cells in lyn-deficient mice. 1. Exp. Med. 184,831-838. Ward, S. G., June, C. H., and Olive, D. (1996). PI 3-kinase: A pivotal pathway in T-cell activation? Immunol. Today 17, 187-197. Weiss, A., and Littman, D. R. (1994).Signal transduction by lymphocyte antigen receptors. Cell 76, 263-274. Weng, W. K., Jarvis, L., and LeBien, T. W. (1994). Signaling through CD19 activates Vadmitogen-activated protein kinase pathway and induces formation of a CD19Navl phosphatidylinositol 3-kinase complex in human B cell precursors. J. Bid. Chem. 269, 32514-32521. Wirthmueller, U., Kurosaki, T., Murakami, M. S., and Ravetch,J. V. (1992).Signal transduction by Fc gamma RIII (CD16) is mediated through the gamma chain. 1. Exp. Med. 175, 1381-1390. Yamanashi, Y., Fukuda, T., Nishizumi, H., Inazu, T., Higashi, K., Kitamura, D., Ishida, T., Yamamura, H., Watanabe, T., and Yamamoto, T. (1997). Role of tyrosine phosphorylation of HS1 in B cell antigen receptor-mediated apoptosis. J. Exp. Med. 185, 1387-1392. Yang, W., and Desiderio, S. (1997). BAP-135, a target for Bruton’s tyrosine kinase in response to B cell receptor engagement. Proc. Natl. Acad. Sci. U.S.A. 94, 604-609. Yao, L., Suzuki, H., Ozawa, K., Deng, J., Lehel, C., Fukamachi, H., Anderson, W. B., Kawakami, Y., and Kawakami, T. (1997). Interactions between protein kinase C and pleckstrin homology domains. Inhibition by phosphatidylinositol 4,5-bisphosphate and phorbol 12-myristate 13-acetate.J. Biol. Chem. 272, 13033-13039. Yi, T., and Ihle, J. N. (1993). Association of hematopoietic cell phosphate with c-Kit after stimulation with c-Kit ligand. Mol. Cell. Biol. 13, 3350-3358. Yi, T., Mui, A. L., Krystal, G., and Ihle, J. N. (1993). Hematopoietic cell phosphatase associates with the interleukin-3 (IL-3) receptor beta chain and down-regulates IL-3induced tyrosine phosphorylation and mitogenesis. Mol. Cell. Biol. 13, 7577-7586. Yi, T., Zhang, J., Miura, O., and Ihle, J. N. (1995).Hematopoietic cellphosphatase associates with erythropoietin (Epo) receptor after Epo-induced receptor tyrosine phosphorylation: Identification of potential binding sites. Blood 85, 87-95. Yokoyama, W. M., and Seaman, W. E. (1993). The Ly-49 and NKR-P1 gene families encoding lectin-like receptors on natural killer cells: The NK gene complex. Annu. Reu. lmmunol. 11, 613-635.

INHIBITION BY ITIM-CONTAINING RECEPTORS

177

Yu, Z., Su, L., Hoglinger, O., Jaramillo, M. L., Banville, D., and Shen, S . H. (1998). SHP1 associates with both platelet-derived growth factor receptor and the p85 subunit of phosphatidylinositol 3-kinase. 1.Biol. Chem. 273, 3687-3694. Yuasa, T., Kubo, S . , Yoshino, T., Ujike, A., Matsumura, K., Ono, M., Ravetch, J. V., and Takai,T. (1999). Deletion of FcyRllB renders H-2bmice susceptible to collagen-induced arthritis. /. Exp. Med., in press. Zhang, R., Alt, F. W., Davidson, L., Orkin, S. H., and Swat, W. (1995). Defective signalling through the T- and B-cell antigen receptors in lymphoid cells lacking the vav protooncogene. Nature 374,470-473. This article was accepted for publication on August 28, 1998.