From antigen to activation: specific signal transduction pathways linking antigen receptors to NF-κB

Seminars in Immunology 15 (2003) 177–183

From antigen to activation: specific signal transduction pathways linking antigen receptors to NF-␬B Jürgen Ruland a,b , Tak W. Mak a,∗ a

Advanced Medical Discovery Institute, Ontario Cancer Institute and University of Toronto, 620 University Avenue, Toronto, Ont., Canada M5G 2C1 b Third Medical Department, Technical University of Munich, Klinikum rechts der Isar, Ismaninger Str. 22, 81675 Munich, Germany

Abstract A precise balance between cellular apoptosis and cellular survival is essential for the proper functioning of the immune system. Whereas apoptosis eliminates self-reactive or supernumerary lymphocytes, survival signaling that counteracts apoptotic programs is needed to allow B and T lymphocytes that recognize pathogens to become activated and expand in response to infection. A major regulator of lymphocyte survival and activation is the transcription factor NF-␬B. Controlled activation of NF-␬B is essential for normal innate and adaptive immune responses, and dysregulated NF-␬B signaling in lymphocytes contributes to diseases ranging from chronic inflammation and autoimmunity to lymphoma. The core NF-␬B activating machinery composed of the NF-␬B, I␬B and IKK proteins is relatively well-characterized, but it is less clear how distinct upstream stimuli activate NF-␬B in a tissue-, time- and signal-specific manner. In this review, we discuss recent insights into the specific signal transduction pathways leading to NF-␬B activation that are triggered by engagement of the antigen receptors of T and B cells. We focus mainly on T cell receptor (TCR)-mediated NF-␬B activation and draw parallels to B cell receptor (BCR)-mediated NF-␬B activation where appropriate. © 2003 Published by Elsevier Science Ltd. Keywords: Lymphocyte; Antigen receptor; Signal transduction; NF-␬B; BCL10

1. Introduction The transcription factor NF-␬B is a central orchestrator of both innate and adaptive immune responses. In lymphocytes, NF-␬B positively regulates cell survival and controls activation, proliferation and effector function through the transcriptional activation of a wide variety of ␬B sitecontaining target gene [1]. These genes encode a plethora of immunomodulatory factors, including cytokines, chemokines, adhesion receptors, anti-microbial peptides, cell cycle regulators and potent anti-apoptotic proteins. NF-␬B is not a single molecule but a small family of dimeric DNA binding proteins. Five NF-␬B family members exist in mammals: RelA (p65), RelB, c-Rel, NF-␬B1 (p50 and its precursor p105) and NF-␬B2 (p52 and its precursor p100). They can exist as either homo- or heterodimers and share a conserved N-terminal, 300 amino acid Rel-homology domain responsible for dimerization, nuclear translocation, DNA binding and activation of gene transcription [2]. The predominant NF-␬B species in many cell types (including mature lymphocytes) is a RelA:p50 heterodimer. ∗ Corresponding

author. Tel.: +1-416-204-2236; fax: +1-416-204-5300. E-mail address: [email protected] (T.W. Mak).

1044-5323/03/$ – see front matter © 2003 Published by Elsevier Science Ltd. doi:10.1016/S1044-5323(03)00034-4

The activity of NF-␬B is tightly regulated by a collection of I␬B inhibitory proteins. I␬B family members are characterized by the presence of multiple ankyrin repeats that mediate protein–protein interactions. The three conventional isoforms of I␬B are I␬B␣, I␬B␤ and I␬Bε, but the NF-␬B precursor proteins p100 and p105 can also function as I␬Bs [2]. In unstimulated cells, NF-␬B dimers are bound to I␬Bs which retain them in an inactive state in the cytoplasm. Upon cellular stimulation, signals are transduced that lead to the degradation of I␬B and the freeing of NF-␬B. NF-␬B then stably translocates to the nucleus and initiates gene transcription. I␬B degradation is triggered by the phosphorylation of two conserved N-terminal serine residues, an event which marks the I␬B protein for ubiquitination and subsequent proteolysis by the 26S proteasome. I␬B phosphorylation is catalyzed by the multiprotein I␬B kinase (IKK) complex that contains two homologous catalytic subunits (IKK␣ and IKK␤) and the regulatory subunit IKK␥/NEMO [3]. Gene targeting experiments in mice have demonstrated that the IKK␤ and IKK␥ subunits are essential for the activation of the canonical NF-␬B pathway in response to pro-inflammatory stimuli such as bacterial lipopolysaccharide (LPS), TNF-␣, IL-1 and antigen [4–10]. In contrast, IKK␣ is involved in a specialized alternative

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Fig. 1. The classical NF-␬B signaling module composed of NF-␬B, I␬B and IKK proteins. NF-␬B activation can be triggered by many distinct upstream stimuli. The point of convergence is the IKK complex which is composed of the two catalytic subunits IKK␣ and IKK␤ and the regulatory subunit IKK␥. IKK phosphorylates I␬B and induces its ubiquitination and degradation, freeing NF-␬B to translocate into the nucleus and activate gene transcription. See text for more details.

mechanism for NF-␬B activation that is independent of both IKK␤ and IKK␥ [11]. This pathway controls basal NF-␬B2/p100 processing in mature B cells [12,13] as well as ligand-induced p100 processing mediated by BAFF, CD40L and lymphotoxin ␤ [14–16]. In addition, IKK␣ regulates epidermal differentiation independent of NF-␬B [17–19]. The axis of I␬B, NF-␬B and IKK proteins can be seen as a core signaling module that controls NF-␬B activation in response to a wide variety of upstream stimuli (Fig. 1). These stimuli include ligands binding to pro-inflammatory cytokine receptors (e.g. TNF-R or IL-1-R), Toll-like receptors (TLRs) or antigen-specific T and B cell receptor (TCR, BCR) complexes, all surface molecules that alert immune system cells to the presence of infection. Each of these separate receptor systems utilizes a distinct array of adapter molecules and signaling enzymes to mediate IKK and NF-␬B activation in a signal-, cell- and time-specific manner. This process often involves recruitment of the IKK signalosome to the activated receptor complex at the cell membrane [20–22]. The signaling molecules and pathways that activate NF-␬B in response to TNF-␣ or IL-1 are relatively well established [23]. However, we are only now beginning to understand how engagement of the antigen receptor complexes of T and B cells induces IKK and NF-␬B activation. We will now discuss recent progress in defining the signal transduction pathway that links T cell receptor ligation to

NF-␬B activation and draw parallels to the B cell receptor system.

2. Signal initiation by the TCR complex and propagation through protein kinase C␪ (PKC␪) After the TCR binds to peptide-major histocompatibility (MHC) complexes on antigen presenting cells (APCs) or target cells, intracellular signaling is initiated with the activation of TCR-associated protein tyrosine kinases such as Lck, Fyn and ZAP-70 (Fig. 2). These enzymes phosphorylate various adapter proteins, including LAT, SLP-76 and Grb2, and signaling molecules such as Vav and phospholipase C␥ (PLC␥) [24]. Together with signals from costimulatory and adhesion receptors such as CD28 and LFA-1, these early events induce the formation of highly organized supramolecular activation clusters (SMACs) at the contact site between the T cell and APC. SMACs then serve as signaling platforms to activate the multiple downstream signal transduction pathways that culminate in T cell activation. The activation of NF-␬B by TCR/CD28 costimulation has been shown to depend on the function of ZAP-70, SLP-76 and Vav [25,26]. However, these receptor proximal molecules not only trigger the NF-␬B pathway but also control the activation of downstream effectors such as the ERKs, NF-AT and AP-1 [27].

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Fig. 2. The specific T cell receptor-mediated NF-␬B activation pathway. After TCR and CD28 stimulation and immune synapse formation, PKC␪ translocates to the TCR signaling complex (1) and initiates recruitment of CARMA1 and BCL10 into the lipid rafts (2). An unknown mechanism (?) then leads to the activation of the IKK complex (3) and ultimately to NF-␬B activation. See text for details.

Directly downstream of receptor proximal signaling is protein kinase [28], a Ca2+ -independent PKC isoenzyme primarily expressed in T lymphocytes and skeletal muscle [29]. PKC␪ is the only PKC isoform that is recruited into the immunological synapse. PKC␪ recruitment is mediated by a Vav/Rac-dependent mechanism [30] and results in the distribution of PKC␪ into lipid rafts, membrane microdomains that concentrate critical signaling mediators. Earlier studies in cell lines demonstrated that PKC␪ couples TCR signaling to expression of the IL-2 gene [31,32], the promoter of which contains consensus binding sites for AP-1, NF-␬B, NF-AT and Oct [33]. It was also shown that PKC␪ stimulates AP-1 activity in T cells [34] via c-Jun N-terminal kinase (JNK) [31,32,35]. More recently, however, several groups have independently reported that PKC␪ also controls NF-␬B activation induced by TCR/CD28 stimulation [36–38]. The essential and specific role of PKC␪ in TCR signaling has been genetically demonstrated using gene-targeted mice in which the PKC␪ gene was inactivated (PKC␪−/−mice) [39]. While the lymphocytes of PKC␪−/−mice developed normally, peripheral T cells isolated from these animals failed to produce IL-2 or proliferate in response to TCR ligation. Whereas receptor proximal signaling and MAP kinase and NF-AT activation were normal in PKC␪−/−T cells, neither AP-1 nor NF-␬B could be activated after TCR ligation, confirming that PKC␪ regulates both these transcription factors. PKC␪-mediated regulation of NF-␬B activity was found to be TCR signal-specific, since TNF-␣ and IL-1 were able to induce NF-␬B DNA binding activity in wildtype and PKC␪−/−T cells to a similar extent. Mechanistic insights into how PKC␪ induces NF-␬B activation have come from concurrent biochemical studies

[21,37]. PKC␪ activation in response to TCR/CD28 signaling results in the recruitment of the IKK complex into the lipid raft fraction associated with the ligated TCR [21] and the selective activation of IKK␤ but not IKK␣ [37]. This latter finding is consistent with genetic data from IKK-deficient mouse models in which IKK␤ was shown to be the essential catalytic IKK subunit for TCR-induced proliferative responses [9]. In contrast, the IKK␣ subunit was dispensable for both T cell development and T cell proliferation in response to TCR ligation and a variety of other stimuli [12]. Since PKC␪ is only minimally expressed in B cells, BCR signaling depends on a different PKC isoenzyme, most likely the conventional PKC isoform PKC␤ [20,40]. PKC␤ activity in response to BCR engagement depends on both diacylglycerol (DAG) production and calcium signaling which are regulated by Bruton’s tyrosine kinase (Btk) [41]. Both X-linked immunodeficiency (XID) mice, which have an inactivating mutation in the Btk gene, as well as PKC␤−/−mice have reduced numbers of peritoneal B1 cells and a defect in T-independent type 2 (TI-2) B cell responses [42–44]. More recent analyses have determined that both Btk and PKC␤ are critical mediators of NF-␬B activation in response to BCR engagement, and that PKC␤ acts downstream of Btk [20,40,45,46]. Like PKC␪ in T cells, PKC␤ controls recruitment of the IKK signalosome into the immunoreceptor-associated lipid raft fraction and mediates IKK activation upon BCR engagement. Interestingly, a therapy-refractory subset of non-Hodgkin’s lymphomas expresses high levels of PKC␤ and exhibits constitutive NF-␬B activation. This observation implies that survival signaling involving PKC␤-dependent

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NF-␬B activation can contribute to B cell malignancy [47,48].

3. Signal transduction through the caspase recruitment domain (CARD) proteins BCL10 and CARMA1 Although TCR- and BCR-mediated NF-␬B activation require specific PKC isoforms, both pathways utilize a common downstream adapter molecule to activate the IKK complex. This protein contains a caspase recruitment domain and is called BCL10 (B cell leukemia/lymphoma 10, also known as CIPER, CARMEN, mE10, CLAP and c-E10) [49–54]. BCL10 was originally identified from the recurrent chromosomal translocation breakpoint t(1;14)(q22;q32) in B cell lymphomas of the mucosa-associated lymphoid tissue (MALT) type [49,50]. The translocation brings the BCL10 gene under the control of the immunoglobulin heavy chain enhancer, and leads to BCL10 overexpression. Mice deficient for Bcl10 are severely immunocompromised [55]. Despite normal numbers and distribution of peripheral T and B cells, these mutant animals have dramatic reductions in the concentrations of all serum immunoglobulin isotypes and show severely impaired B and T cell responses to infections in vivo. In vitro, isolated T or B cells from Bcl10 −/−mice do not proliferate when stimulated through the antigen receptor. However, Bcl10−/−B cells can be activated with bacterial endotoxin (LPS), a stimulus which signals through the innate receptor TLR4 [56]. Bcl10−/−T cells do not proliferate partly because of a deficiency in IL-2 production and a failure to upregulate CD25, the high affinity subunit of the IL-2 receptor. Biochemical analysis of TCR signaling revealed that receptor proximal tyrosine phosphorylation, calcium mobilization, ERK-MAP-kinase activation and AP-1 induction were all Bcl10-independent. However, in the absence of Bcl10, NF-␬B could not be activated in lymphocytes stimulated either through TCR/CD28 engagement or BCR stimulation. Moreover, Bcl10 was not required for TNF-␣, IL-1 and LPS signaling, suggesting that Bcl10 specifically links antigen receptor signaling to NF-␬B activation. Biochemical analyses showed that Bcl10 operates as an upstream regulator of the IKK complex. The signaling defect associated with Bcl10 deficiency could not be overcome in either T or B cells by treatment with PMA or PMA plus calcium ionophore, stimuli which directly activate PKC isoforms and bypass antigen receptor proximal signaling events. This observation indicates that Bcl10 acts downstream of or at the level of the PKCs. The fact that TCR-induced AP-1 activation, which depends on PKC␪, is normal in Bcl10−/−T cells implies that Bcl10 controls only the PKC␪ effector pathway leading to NF-␬B activation and not that activating AP-1. Whether a similar bifurcation of the signaling pathway exists downstream of PKC␤ in B cells remains to be shown. A functional bridge between PKC activation and Bcl10 in the context of TCR signaling is CARMA1, a member of the

recently identified family of CARD-containing MAGUK proteins. This family also includes CARMA2 (CARD14 or Bimp2) and CARMA3 (CARD10 or Bimp1) [57–60]. The CARMA proteins bind directly to Bcl10 through homophilic CARD–CARD interactions. In addition to their CARDs, these molecules exhibit a coiled-coil domain and a carboxyterminal array of protein–protein interaction modules: one to three PDZ domains, an SH3 domain and a GUK domain. Overexpression of CARMA proteins activates NF-␬B in wildtype cells but not in Bcl10−/−cells [57], suggesting that the CARMA proteins are upstream regulators of Bcl10. The three CARMA proteins have distinct tissue distribution patterns, with CARMA1 being expressed mainly in lymphoid tissues (including thymus, spleen and peripheral blood leukocytes). An elegant genetic study by Wang et al. (2002) provides conclusive evidence that, like PKC␪ and Bcl10, CARMA1 is essential for TCR-mediated signal transduction leading to NF-␬B activation [61]. Wang and colleagues used somatic mutagenesis to generate a Jurkat T cell line that was specifically deficient in CARMA1. The mutant T cells showed defects in TCR/CD28-mediated NF-␬B activation as well as in IL-2 expression, but TNF-␣ signaling leading to NF-␬B activation was normal. The defect in CARMA1-deficient T cells was found to lie downstream of PKC␪, and it was further demonstrated that CARMA1 connects PKC␪ to Bcl10. A parallel study by Pomerantz et al. used RNA interference and deletion mutants of CARMA1 to obtain comparable results [62]. In addition to showing that CARMA1 mediates TCR-specific activation of NF-␬B but not AP-1 or NF-AT, this study also demonstrated that CARMA1 cooperates directly with Bcl10 to activate the IKK complex. The CARD, coiled-coil, SH3 and GUK domains were all found to be necessary for normal signaling function. The overexpression of a dominant negative (DN) version of CARMA1 in T cell lines has provided some mechanistic insight into CARMA1 function [63]. In addition to also demonstrating the necessity for and specificity of CARMA1 in TCR-mediated NF-␬B activation, Gaide et al. showed by confocal microscopy that CARMA1 is diffusely distributed in the plasma membrane and submembraneous cytoplasmic compartments of unstimulated T cells. Upon aggregation of CD3, however, CARMA1 is transiently recruited into the lipid rafts associated with the TCR signaling complex. In addition, a small fraction of Bcl10 co-translocates with its binding partner CARMA1 into the lipid raft fraction. (In unstimulated cells, Bcl10 is excluded from the rafts.) Taken together, the three studies cited immediately above imply a model in which CARMA1 serves as a scaffolding protein that assembles higher order signaling complexes at the immunological synapse. Since MAGUK proteins bind primarily to the cytoplasmic tails of transmembrane proteins [64], it is conceivable that CARMA1 uses its carboxyterminal array of PDZ, SH3 and GUK motifs to associate with lipid raft-embedded factors of the activated TCR complex. CARMA1 could then recruit Bcl10 into the lipid raft fraction via CARD binding in an activation-dependent manner.

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Whether CARMA1 is also required for BCR signaling remains to be shown. The immediate molecular events downstream of CARMA1 and Bcl10 interaction that lead to IKK activation are still unclear. Bcl10 does not bind directly to IKK␥/NEMO like other adapter proteins involved in NF-␬B activation [65], suggesting that there are one or more signaling intermediates between Bcl10 and IKK. One molecule that has been implicated in Bcl10 signaling is MALT1 (also known as MLT). Like Bcl10, MALT1 was originally identified from a recurrent chromosomal translocation in MALT lymphomas [66–68]. The t(11;18) breakpoint fuses the C-terminus of the MALT1 protein to the N-terminus of API2. MALT1 is distantly related to the caspase family of cysteine proteases and is therefore referred to as a mammalian paracaspase [69]. Wildtype MALT1 protein contains an N-terminal prodomain composed of a death domain and two Ig-repeats, and a C-terminal region that resembles the catalytic domain of caspases [69]. However, MALT1 does not function as a traditional caspase [65,69]. Instead, MALT1 binds directly to Bcl10 via its two Ig-repeats and the two proteins form a subcellular complex that cooperates in the activation of NF-␬B. Whereas overexpression of wildtype MALT1 does not by itself activate NF-␬B, co-overexpression of Bcl10 and MALT1 strongly enhances Bcl10-induced NF-␬B activation in 293T cells. Moreover, overexpression of lymphoma-associated API2-MALT1 fusion proteins in cell lines can induce vigorous NF-␬B activation. Additional in vitro work has shown that the caspase-like domain of MALT1 must be intact for NF-␬B activation [65,69]. Point mutants of MALT1 in which the conserved cysteine in the paracaspase domain is replaced by an alanine showed a reduction in activity. The sum of these data suggests that Bcl10 and MALT1, which are independently involved in MALT lymphoma translocations, may cooperate in a common NF-␬B signaling pathway. However, the physiological nature of this pathway remains unclear. It is unknown whether MALT1 is required for Bcl10-mediated regulation of antigen receptor signaling, and if so, whether MALT1 plays distinct or overlapping roles in T and B lymphocytes. The relationship between MALT1 and the IKK complex is also still a mystery. The answers to these questions may be of considerable relevance, since Bcl10 and MALT1 may represent valuable drug targets for the treatment of MALT lynmphomas. The generation and analysis of MALT1-deficient mice will help to define the precise function of this paracaspase.

4. Conclusion and future prospects Over the past two years, our understanding of the molecular pathways specifically linking T and B cell antigen receptor signaling to NF-␬B activation has increased substantially. These pathways are of central importance for T and B cell-mediated immune responses and are often aber-

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rantly upregulated in human lymphomas. In the latter case, excessive NF-␬B activation presumably leads to increased cell survival which favors lymphomagenesis. NF-␬B is already one of the most attractive drug targets under consideration for immunosuppressive and anti-inflammatory therapies, and perhaps even for the treatment of leukemia and lymphoma. However, since NF-␬B operates in a wide variety of cells and tissues and acts to prevent inappropriate apoptosis, a general inhibition of NF-␬B activity is expected to be associated with major detrimental side-effects. More favorable outcomes would likely be achieved by targeting NF-␬B activation in a context-specific manner. Based on the lymphocyte-restricted phenotypes of PKC␪, PKC␤ and adult Bcl10-deficient mice, we anticipate that a specific blockage of this signaling cascade would have relatively limited in vivo toxicity. This newly defined pathway leading from antigen to NF-␬B activation therefore seems to be an ideal drug target for novel immunosuppressive regimens as well as for the treatment of selected lymphoid malignancies.

Acknowledgements The authors thank Mary Saunders for scientific editing.

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