Recognition structures on natural killer cells

Recognition

structures Wayne

Mount

have identified

cell surface

activation

such as NKR-PI

‘receptors’,

by transducing

molecules

presumably

with

structures

have

molecules,

such as Ly-49

not

been

elucidated.

Ly-49

natural

molecules

killer

Natural

cell cytotoxic

polymorphic

gene families

on the distal

region of mouse

systems.

Thus,

determined

killer

in rodents,

signals.

ligands cells

similar

the specificity system

The

and

display

chromosome

other

receptors

NKR-PI

by

killer

6. Additional

functionally

of an individual

repertoire

murine

encoded

in the natural

defined and studied

These

but these

and deliver signals, negatively

activity.

that reside

by its expressed

of this recognition

molecules

biochemical

in mice, that appear to be ‘inhibitory’

are structurally

been serologically

USA

that appear to play

target cell surface

that engage target cell MHC class I molecules regulating

cells

for their targets. Natural killer

that may activate cytotoxicity interact

New York,

molecules

roles in natural killer cell specificity

cells display

killer

M. Yokoyama

Sinai Medical Center, New York,

Recent studies important

on natural

natural

of

gene complex molecules

in murine killer

of these molecules.

and

members

have

and human cell may be

The complexities

are beginning to be appreciated at the molecular level.

Current

Opinion

in Immunology

1993,

5:67-73

Introduction

Activation

‘receptors’

Natural killer (NK) cells constitute a small population of lymphocytes that generally display a large, granular morphology and are found in peripheral lymphoid tissues and blood. NK cells are functionally defined as having ‘natural’ cytolytic activity against certain tumor and virally infected cells [l-3]. The molecular basis for NKcell recognition and activation by target cells has not been elucidated. NK cells are distinguished from other lymphocytes by the absence of B- and T-cell antigen receptors, i.e. surface Ig and T-cell receptor (TCR), respectively. AL though freshly isolated NK cells express the < chain of the CD3/TCR complex [4,5], they do not display other components of the complex, do not express mRNA for mature TCR chains and do not rearrange TCR genes [6]. Since physical contact is required for spontaneous qtotoxicity, the molecular basis for reactivity of NK cells with their targets should involve effector cell surface molecules that engage cell surface structures expressed on target cells. In order to account for the undefined specificity of NK cells, these molecules may display complex polymorphism. Moreover, recent studies have suggested that NK cells appear to express surface molecules that not only activate cytotoxicity but also inhibit killing; NK-cell specificity may be regulated by both types of molecules.

On NK cells, the Fc receptor for IgG (FcyRIII or CD161 can bind the Fc portion of antibodies coating a target cell. This may lead to NK-cell activation and lysis of the target, i.e. antibody-dependent cellular cytotoxicity (ADCC) [7,8]. NK cells also can be activated to lyse targets through the CD2 molecule [9-l 1] However, neither CD16 nor CD2 appears to play an important role in natural killing because NK cells that lack either antigen can still perform spontaneous qtotoxicity [3,7,12]. Recent studies provide evidence supporting the role of other molecules in rodent NK-cell activation. The disulfide-linked homodimer, NKRPl, (30 kD subunits) is recognized by monoclonal antibody (mAb) 3.2.3 and is expressed by all rat NK cells [ 131. MAb 3.2.3 stimulates NK cells to lyse otherwise resistant target cells [ 131. Originally described for activation of T-cell clones by mAbs specific for the CD3/TCR complex [ 141, stimulation of NK cells to lyse resistant targets occurs in a phenomenon termed redirected lysis where, in opposite orientation to ADCC, the mAb binds specifically to the effector cell. Its Fc portion binds to a target cell Fc receptor that provides a bridging and cross-linking effect. The mAb thus initiates lysis by stimulation through the effector cell antigen. Because redirected lysis occurs only through selected cell

Abbreviations ADCC-antibody-dependent HLA-human MCMVP-mouse

cellular

leukocyte-associated

cytomegalovirus; RFLP-

antigen;

MHC-major restriction

cytotoxicity;

CM-centimorgans;

Ig-immunoglobulin;

histocompatlbility fragment

@

Current

complex;

length polymorphism;

Biology

Hh-hemopoietic

IL-interleukin; NK-natural

mAb_ killer;

histocompatibility; monoclonal

NKG

natural

antibody; killer gene complex;

TCR-- -T-cell receptor.

Ltd 0952-7915

67

68

Innate

immunity

surface antigens, it highlights a relatively unique functional property of the cell surface molecule. Consistent with this, mAb 3.2.3 stimulates release of serine esterases [ 131. Moreover, it activates phosphoinositide turnover and increases levels of intracellular calcium in NK cells [15-l. Similar biochemical events occur when NK cells are exposed to their susceptible targets [ 161. These results are consistent with the hypothesis that NKR-Pl plays a role in activating NK ceils. The putative NKRPl polypeptide is a type II integral membrane protein, with its carboxyl terminus exposed [ 171. Rat NKR-Pl has significant homolextracetlularly ogy (22% identity) with members of the C-type lectin superfamily, including the low affinity Fcareceptor ( FcEKII or CD23 1, hepatic asialoglycoprotein receptor and the mouse Ly-49 molecule (see below). The functional relevance of the homology of NW-P1 with the C-type lectins is unclear, but several members of this superfamily bind to specific carbohydrates in a Caz+ -dependent manner

1181. In the mouse, the NK1.l antigen, identified by mAb PK136 [ 191, displays allelic polymorphism, and on CD3lymphocytes, has long been considered the most specific serological marker for murine NK cells [6]. MAb PK136 triggers NK cells to kill targets in a manner consistent with redirected lysis [ 20*]. Although interleukin (IL)-2-activated NK cells possess other structures (i.e. my-6 and VEA) through which redirected lysis can be triggered, freshly isolated NK cells can be stimulated only through NK1.l [20*]. The mouse NK1.l and rat NKR-Pl molecules are similar with regard to selective expression on NK cells, disulfide~ linked homodimeric structure and ability to transmit activation signals. In view of these similarities, it was hypothesized that a mouse form of NKIGPl may be the NK1.l antigen. Two groups isolated cDNAs encoding the mouse NKRPl molecule by screening cDNA libraries with the rat NKR-Pl probe [ 21**-23**]. Several of these cDNAs were homologous but not identical whereas other cDNAs appear to be identical except for small deleted DNA segments. This suggests that NKRPl is expressed in multiple, related forms. Infection of insect cells with a baculovirus construct containing one of the cDNAs resulted in expression of the NK1.l antigen, which was retognized by rnAb PK136, determined using flow cytometry and immunoprecipitation [ 21**]. Thus, the NKl.l antigen represents one form of the mouse NKR-Pl family of molecules. The NKRPl molecules share features with those expected of an NK-cell receptor that is responsible for NK-cell activation in spontaneous cytotoxicity, i.e. expression that is restricted to NK cells, polymorphism, and activation of cytotoxicity and the biochemical events associated with spontaneous cytotoxicity. However, the NKR Pl molecules have not been shown yet to be responsible for natural killing. MAbs against these molecules do not block spontaneous cytotoxicity and NK-cell mutants that lack these molecules are just beginning to be studied. These approaches may be complicated because an NK cell may express multiple forms of these molecules

[ 21**-23**], A mAb may not block qtotoxicity or a mutant NK cell lacking an NKR-PI molecule may continue to kill because other homologous molecules could potentially substitute for the blocked or absent NKF-PI molecule. A putative ligdnd for an NKR-PI form has not been identitied. If NKRPl is the ‘activation’ receptor responsible for natural killing, then NK-cell susceptible targets should display its l&and. Because NKRPI is polymorphic, the ligands may be different fc)r each individual NKR-Pl form and/or the NKR-P 1 ligand itself may belong to a family of polymorphic molecules.

Inhibitory

‘receptors’

MHC class

I molecules and NK cells Most early studies of heterogeneous populations of NK cells suggest that NK-cell activity is not ‘restricted’ by specific MHC antigens on target cells [l&3], However, more recent studies suggest that there is an inverse correlation between the expression of certain MHC class I molecules by target cells and susceptibility to NK cell mediated lysis. Several MHC class I negative mutant cell lines are more susceptible to NK cell mediated lysis than the parental cells [ 24-261. Moreover, resistance to NK cell mediated lysis can be restored by reconstitution of MHC class I expression with transfection of the Pz-microglobulin gene [27-29,301. The gene transfer and expression of a single MHC class I molecule, in some cases, is sufficient to confer relative resistance to heterogeneous NK pop&dtions [ 26,31,32]. Although this correlation has not been demonstrated for other targets [33-351, human studies [ 26,361 suggest that expression of only certain MHC class I molecules is rebated to the resistant phenotype. In zizjo corroboration for these in ritro findings has been obtained in experiments using P2-microglobulin-delicient transgenic mice that lack normal expression of MHC class 1 molecules [37**-39**]. In contrast to cells from normal mice, cells from these mice were susceptible to natural killing. Moreover, in a manner that resembles the phenomenon of hybrid resistance, bone marrow from these mice could not engraft lethally irradiated MHC-matched normal mice [37**,39**]. This rejection is mediated by host NKl.l + cells. In hybrid resistance, parental bone marrow is rejected in lethally irradiated Fl hybrid mice by NK cells [40], The genes encoding the antigens that mediate hybrid resistance on donor bone marrow cells, i.e. hemopoietic histocompatibility (Hh)-1 antigens, have been mapped to the MHC region, near the H-2D locus [41]. Bone marrow cells from H-2h mice transgenic for H-2Dd. are able to engraft (H-2Dh X Hm2Dd)F1 hybrid mice [42], compatible with the possibility that the MHC class I locus, H-2D, is inversely responsible for hybrid resistance. Parental bone marrow is rejected in Fl hybrid mice presumably because the parental bone marrow lacks the full compiement of MHC class I molecules expressed by Fl hybrid mice. Although it remains possible that another gene, or regulatory element cosegregates with H-2D, and accounts for hybrid resistance, taken to-

Recognition

gether, the data generally indicate that target cell MHC class I expression correlates inversely with susceptibility to NK cell mediated lysis. Cells from the &-microglobulin-deficient transgenic mice were not killed by their own NK cells in zk?ro,suggesting that factors other than target cell MHC class I expression may regulate self versus non-self discrimination by NK cells [38**,39-1. Alternatively, normdl MHC class I expression may be required for development of fully competent NK cells. Compared with NK cells from normal mice, NK cells from these mice have relatively impaired killing of NK cell tumor targets. Thus, future studies of Pi-microglobulin-deficient transgenic mice may provide further insight into natural killing and hybrid resistance. Detailed analyses of human MHC class 1 interaction with NK cells have been performed [26,36,43**]. Experiments in which exon-shuffled HLA class I molecules were transfected into target cells have implicated the al/a2 domains of MHC class I in interactions with NK cells. Mutational analysis [43**] demonstrated that a single amino acid substitution (residue 74) in the al helix of HIAA2 converted target cells to an NK cell resistant phenotype, suggesting that the peptide-binding cleft may be involved [44]. Taken together, these studies demonstrate that MHC class I molecules may present peptides to NK cells as well as cytotoxic T cells but with opposite functional consequences because, in contrast to cytotoxic T cells, NK cells are generally less effective against targets that express MHC class I molecules and are more eEective at killing targets that lack MHC expression. An hypothesis has been put forward to explain the inverse correlation of target cell MHC class I antigen expression and susceptibility to NK cell lysis [ 451, NK cells may survey normal tissues for MHC class I molecules; in the absence of normal MHC class I expression, the target is lysed. This may occur through two postulated mechanisms. The MHC antigen may ‘mask’ the target cell antigen responsible for triggering NK cells, thus blocking recognition by NK cells. Alternatively, the MHC antigen may be specifically recognized by an effector cell molecule, triggering a ‘negative’ signal. The masking model requires at least one NK cell receptor that binds target cell structures whereas the negative signailing model requires two receptors, one for activation, and the other for inhibition. Although the masking hypethesis has not been excluded, recent studies support the latter model.

structures

on natural

killer

cells

Yokovama

147.481. This is supported by analysis of cDNAs derived from a (CBA X C57BIjb)Fl hybrid mouse [49*]. However, some of these forms may be due to allelic differences because CBA mice express a different restriction fragment length polymorphic (RFLP) variant to C57BU6 [ib]. my-49 appears to be an inhibitory receptor specific for a target cell MHC class I molecule [50*=]. Ly-49+ and Ly49- NK cells are comparable with respect to cell surface expression of CD16 and NKl.l, and cytolytic capacity; however, the two subsets differ in their specificity. Ly-49+ NK cells do not lyse H-2d and H-2k targets, even though these targets are lysed by Ly-49 NK cells. Transfection and expression of cDNA encoding H-2Dd but not H-2Kd or H-21>’renders a susceptible target resistant to lysis by Ly-49 + NK cells. This resistance is reversed by mAbs specific for Ly-49, and the al/c12 domains of H-2Dd whereas a mAb specific for the c*3 domain of Hm2Dd has no effect. The F(ab’)L forms of the anti-Ly-49 and anti-al/a2 mAbs continue to allow lysis, providing evidence against the possibility of redirected lysis and ADCC, respectively. The mAb studies are consistent with a blocking effect. These results support the hypothesis that upon engagement of Ly-49 on the NK cell with the al/~2 domains of H-2Dd on the target cell, Ly-49 delivers an inhibitory signal to the NK cell. The inhibitory effect of Ly-49 engagement appears to be dominant over activation through multiple pathways including exposure to NK-cell sensitive targets, ADCC, lectin-mediated lysis and redirected lysis with mAbs directed against NK1.l and other structures on IL-2-activated NK cells [ 50.*,51*], These pathways involve distinct structures that are not physically associated on the NK cell surface, suggesting that Ly-49 is a putative inhibitoty receptor that transmits ‘negative’ signals that interrupt or abort these pathways. Although it has not yet been possible to generate longterm mouse NIGcell clones, human NK-cell clones have been derived. These studies demonstrate that NK cells are heterogeneous with respect to capacity to kill targets and indicate that NK cells possess specificities that may differ between individual NK cells [ 52*,53]. Moreover, human NK-cell clones have an apparent allospecificity that maps to the human MHC complex, HL4 [ 541. These results suggest that human NK-cell allospecificity may be determined in a manner similar to regulation of rodent NK-cell c>*otoxicity.

The NK gene complex The Ly-49 cell surface molecule The Ly-49 cell surface antigen is expressed by a subpopulation (15-20%) of splenic NK cells [46]. It is expressed as a disulfide-linked homodimer with 44 kD subunits. Analysis of cDNA encoding Ly-49 revealed that the putative polypeptide is a type II integral membrane protein [47,48] with an external C-type lectin domain [47]. Southern blot analysis suggested that the gene encoding Ly-49 belongs to a family of cross-hybridizing genes

The Ly-49 and mouse NKR-Pl polypeptides share several unique features, including selective expression on NK cells, type II transmembrane protein orientation, and homology to C-type lectins. Moreover, these molecules are functionally active in NK cell mediated lysis. Yet, they have opposing functional effects and are encoded by distinct genes. Using RFLP analysis in recombinant inbred mice, the genes encoding Ly-49 and mouse NKR Pl were found to be separated by only 0.4 centimorgans (CM) on distal mouse chromosome 6 [21**]. Thus, this

69

70

Innate

immunitv

genetic region has been (NKC).

termed

the NK gene complex

Based on the genetic linkage data, the NKR-Pl and Ly49 loci may be physically separated by approximately 500 kilobase pairs. This distance is considerable and the NKC may extend beyond these loci. This suggests that there may be additional genes clustering in this region that may play important functional roles in NK cells, analogous to the MHC complex and antigen presentation. Consistent with this hypothesis, human NK cell specific molecules have been described recently [55*]. The NKG2 cDNAs were isolated by subtractive hybridization and encode type II integral membrane proteins with C-type lectin extracellular domains. These human molecules appear distinct from the rodent Ly-49 and NKR-1’1 molecules, Although this could be due to species dilferences, these human molecules may have homologs encoded in the mouse NKC. With regard to the function of the NKC gene products on NK cells, a single genetic locus, Cmzj-1, has been described that controls susceptiblility to mouse cytomegalovirus (MCMV) infection [56]. MCMV titers are 103-10” times lower in spleens of resistant mice (Cmv 1’ allele) than in susceptible mice (Cmzk lb allele). Depletion of NK cells from resistant mice or resistant bone marrow chimeric mice results in susceptibility and a marked increase in MCMV replication [ 57,58,59**], The Cmzl- 1 locus has been mapped to the NKC [ 59**], within 0.9 CM from Ly-49 and NKR-Pl. This suggests that Cm!)- 1 may encode an NK-cell recognition molecule, perhaps structurally related to Ly-49 and NKRPl, that is specific for MCMV or MCMVinfected cells.

Other

molecules

associated

with NK-cell

specificity Several other NK cell surface molecules have been described that cannot be clearly grouped yet with the molecules described above because their primary structures have not been determined. Nevertheless, these molecules appear to play a role in NK-cell specificity. MAbs have been produced against human NK-cell clones. The antigens recognized by mAb GLl83 and m.Ab EB6 are expressed by subsets of human NK cells that overlap [60,61]. MAbs GL183 and EB6 recognize antigens expressed either as a single chain 55 kD or 58 kD polypeptide or as a 58 kD polypeptide non-covalently associated with a 55kD polypeptide. These antigens are constitu tively expressed and remain stable during NK-cell culture. MAb GL183 enhanced the ability of mAb-reactive NKcell clones to kill human targets. An F( ab’) 2 form of the mAb continued to enhance killing, inconsistent with the redirected lysis mechanism and consistent with a blocking elfect. In contrast, killing of murine targets is blocked by mAb GL183. Similar findings were reported for mAb EB6. The allospecificity of NK-cell clones for human targets has been correlated with the expression of the anti-

gens recognized by these mAbs. NK-cell clones with a given allospecificity appear to be similar with respect to expression of the antigens recognized by mAbs GL183 and EB6. However, expression of these antigens is not totally predictive of allospecificity. One possible explanation for these results is that there are additional molecules related to these antigens. NK cells may display different repertoires of these molecules that influence speciiicit): In the mouse, the antigen recognized by mAb SW5E6 is a disulfide-linked dimer (with subunits of 54kD) that is expressed by about 50 per cent of NK cells [62]. In hybrid resistance, NK cells expressing this antigen appear to mediate rejection of bone marrow cells expressing H2$Hh_ld or H_2f/Hh-If but not H~2tJ/Hh~ll~ However, NK cells that differ in reactivity with mAh 5E6 do not differ in ability to kill NK-sensitive targets, regardless of target cell hdplotype.

Conclusion Recent studies have identified molecules that appear to play important roles in natural killer cell specificity for their targets. The evidence thus far suggests that natural killer cells express receptors that activate cytotoxicity by stimulating ‘positive’ biochemical signals. These receptors presumably bind to target cell surface ligands but these have not been identified. In addition, natural killer cells appear to have receptors that engage specific MHC class I molecuies expressed by target cells. These receptors may deliver inhibitory signals to the natural killer cells. Other molecules may also participate in determining natural killer cell specificity. Finally, all of these molecules may be polymorphic and may not be clonally distributed. Instead, the specificity of a single natural killer cell may depend on the ‘repertoire’ of molecules that it expresses. Thus, natural killer cells have cornplex recognition systems that are just beginning to be unraveled.

References

and recommended

papersof particular mien,

. .. 1.

interest, published are hghlighted as: of special interest of outstanding interest HFKHERMAN ItIS: NK

(cademic

Cells

cmd

reading

within

Otlxr

the annual

~Vut~nrl

perioci of

EffectorCtds.

Press: New York, 1982:1566.

2.

Fwrmt.rx CW, WILTKOI:I’ RH: Functions of the Nuturcrl lm~NTW S’~stem. New York: Plenum Press; 1989:506.

3.

TRINCHIERI

4.

ANLXXWNP, CALIGIU~U M, KI’I’ZJ, SCHLOS~IM~UVS F: CDS-negative Natural Killer Cells Express c TCR as Part of a Novel Molecular Complex. Nutwe 1989, S4 1:159pl 62.

5.

IANWR IL, Yr’ G, PHILUPS JH Co-association of CD5 5 with a Receptor (CDl6) for IgG Fc on Human Natural Killer Cells. Nutwe 1989. 342:803-805.

G: Biology 1989, 47:uw376.

of Natural

Killer Cells. A&, Inzm~nol

Recognition

6.

LEEK

7.

LZNIER LL, RI’I’I‘ENHEKG JJ. PIIII.I.IPSJH: Functional and Biochemical Analysis of CD16 Antigen on Natural Wer Cells and Granulocytes. ,I Imnzlr& 1988. 141:3478-3485.

8

IL, PHII.I.W JH, HACKE’ITJ JK, ‘I‘rvrr M, KI’MAKV: Natural Wer Cells: Definition of a CeU Type Rather than a Function. .f Itnmu~rol 1986, 137.2735-2’39.

RA\X’I’CI~ .p,

KIVT

JP: Fc Receptors.

Aiz?z RL’I*

1991,

Ir~rnzurd

9:+5’ -192. 9.

IO.

SII.ICI&O RF, I’RATT JC, SCHMIIX W, RITZ J, RFINIIEFZEL. Activation of Cytolytic T Lymphocyte and Natural KiUer Cell Function Through the Tl 1 Sheep Erythrocyte Binding Protein ,Vattrro 1985. 317 -428 -+.30. SCOTT

CF JR, BOIENIXK

J&l, VOK~\~EVI

YP,

S. MLIXI~KI,.

MORI~KXO

vation of Human Cytolytic mtlrztd 1989, 142~-tlO5--tll2. 1 I.

12.

13.

Gl). IIOI.LDACK J, LAMWK’I I~I’z J, SCIII.OS~\~AX SF. ActiCells Through CDL/T1 I. ./ InzC.

BoL~{~‘Is RL. ROUZ~MONI) RC, V,ZN DI: Gfue~~ K.1: Induction and Blocking of Cytolysis in CD2+, CD3- NK and CD2 +, CD3+ Cytotoxic T I.ymphocytes Via CD2 50 kD Sheep Erythrocyte Receptor. ,/ frrznrzrr~ol 1986, 1363939~j944. IANIEK Ll., PHWPS JH: A Map of the Cell Surface Antigens Expressed on Resting and Activated Human Natural KiUer cells. In Le&q& _ljpirg II. Edited hy Reinherz EL. New York: Springer Verlag: 1984. 3:157-170. CHAMI~HRS

WH,

~IEKHEI&~

RR,

Vr.I~~o\lc

NL,

DFIXO

AR,

Ouzow

MW.

IS.

IEO 0, SACHS, DII. SAMEL~ON LE. R, BLLIESI’ONE JA: Identification Specific for the T CeU Receptor mediated CTL Lysis. ,J Immud

FOO M, QI.INONES R, GKESS of Monoclonal Antibodies Complex by Fc Receptoi1986, 137:3874- 3880

RYAN JC, NIE%%I EC, GOLDFIEN RD, HISERODT JC, SEAMAN WE NKR-PI, an Activating Molecule on Rat Natural KiUer Cells, Stimulates Phosphoinositide Turnover and a Rise in Intracellular Calcium. ./ fmnzuwol 1997, 147:324&3250. Demonstrates that tngering through NKK-Pl biochemically resembles triggering of NK cells hy their sensitive targets.

15. .

16.

SUMAI% m, ERIKSSON E, IX)RR(Iw R, IMBOI)FN JR: Inositol Trisphosphate is Generated by a Rat Natural Wer Cell Tumor in Response to Target Cells or to Crosslinked Monoclonal Antibody 0X-34: Possible Signaling Role for the OX-34 Determinant During Activation by Target Cells. Proc Nutl Acad Sci USA 1987, 84:+2394243.

17.

GIOKI)A

R, RL’DERT WA,

\‘.4vfiaot~

C. CHAMIXKS

WH,

18.

I~IUCKAMER

19.

Koo GC, P~I’PAI~I)JR. Establishment of Monoclonal 1.1 Antibody. FQhricioma 1981. 3:301-303.

20. .

activated hearing

JC. TIRCh J, NIDII EC. YOK‘X’kVl.4 WM. SFAhlk\ WE Molecular Cloning of the NKl.1 Antigen, a Member of the NKR-PI Family of Natural KiUer Cell Activation Molecules. ,/ I~n”~lrr~(// 1992. l49:16jI_lhj5, One member of the mouse NKR Pl family of molecules bears the epirope recognized hy ;I mAb (PK136) specific for NKl .l. This mAh has long been used to serologically define mouse NK cells (see also [6,9] )

23.

Thus, this study ties together 3 large number of prior studies implicating mouse NK cells (by mAh I’Kl36 depletion, etc.) with the molecular

aspects of NKK Pl m rodems. 24.

by IL-2 can

be

stimulated

by mAhs

directed

to

Iyse

otherwise

against

resistant

25.

26.

LII:NC;C.KEN H G.

PIONTEK

GE,

KI~SSIING

R. KIEIX

PIONIE~

G,

KII:SSI~NC~ R:

STORIU~

WJ,

TANICX~CHI G,

K,

KAIUE

SelecSug1986,

ALIXUIXK

of Natural Transfected

IJIXXXEN

K:

J, PAYW JA, I)Awso~\; JR, CRESSU’EIL

Killing Susceptibility Class 1 HLA Genes.

Expressing Sci I’SA 1989, 86:2361-2364. 27.

Variants Na/rtre

IIC. GRONRERC A, YAC-1 MHC Class I Variants Reveal an Association Between Decreased NK Sensitivity and Increaed H-2 Expression After Interferon Treatment or in Vivo Passage. ,I Immur~ol 1985. 135:42Xl--t288.

1’: Reversal

QL#I~~

A. Pwss~

F, ~(:HIOL-~~~~KNICAIII.T

in Target Cells Proc Nut1 Acad C,

HAZEL-BEI.IAN

A, BEYRI~NA~~~M, PLOEGH

H, FRAI)F.I.IZI D: Increased Resistance to Non-MHC-restricted Cytotoxicity Related to HLA A,B Expression. Direct Demonstration using Beta 2-microglobulintransfected Daudi Cells J fnzmzrnol 1988, 141:17-20.

28.

LII’NGCXEN HG, STI’RIMIIOFEL K, WOIPFX~ E, H.~,WMEIU.IN(; GJ, KARRI;K: Transfection of p2-microglobulin Restores IFN-mediated Protection from Natural Killer CeU Lysis in YAC-1 Lymphoma Variants. .I Immunol 1990, 145:38cC386.

29.

S’III~U#OFEI.

K, HA,u~LEKI.INCI GJ: Reconstitution of H-2 Class I Expression by Gene Transfection Decrease Susceptibility to Natural Wer Cells of an EL4 class I Loss Variant. EZIY ,I In~rllrlrlol 1990. 20:1’1&17’. MAIO M. AISOMONTE M, ‘I’ATAKE K, 2%‘~ RA, FERROKE 5: Reduction in Susceptibility to Natural Killer Cell-mediated Lysis of Human FO-1 Melanoma Cells after Induction of HLA class I Antigen Expression by Transfection with B2m Gene. ,I Clin IVI/KQ 1991, g&282&289

jl.

SHI~WI%IIY, IXMARS

j2.

CAIUO~ DA, PAYNE II, HOZUMI N, RODFR JC, CZII’KOM AA: Class I (H-2Kb ) Gene Transfection Reduces Susceptibility of YAC-I Lymphoma Targets to Natural Wer Cells. Eur .J Imrnuwol 1990, 20:84-~846.

sj.

NISHI~~~~KA MI, STROYNO~SKI

targets

the

\*‘M, RYE JC, HrlNTER JJ, SMITH HRC, s’rm M, SEAMAVWE: cDNA Cloning of Mouse NKH-PI and Genetic Linkage with Ly-49. Identification of a Natural Wer CeU

KARKL~ K,

tive Rejection of H-2.deficient Lymphoma gests Alternative Immune Defense Strategy j 19:675+78.

KARLHOFER

Fc receptors

Ry.4\

. .

ural

NKl. I, Ly~6 and VEA antigens. 1lowever, freshly isolated NK cells can only be stimulated h\ the anti-NK1.l mAb. Thus, the functional proper&s and expression tk mouse NKI.1 antigen resemble that of rdt NKR-PI molecule. 21. ..

to he encoded by distinct genes that may undergo alternatwe splicing, wggestmg rhdt NKR PI molecules may belong I0 a polymorphic family.

Anti-NK-

FM, YOKOYAMA WM: Stimulation of Murine NatKiller (NK) Cells by a Monoclonal Antibody Specific for the NKl.1 Antigen. IL-2 Activated NK Cells Possess Additional Specific Stimulation Pathways. J Inzmunol 1991, 146: j662-j6? j. that NK cells Using the redirected lysis assay, the authors demonstrate

71

cells Yokoyama

G~otw\ R. TRI’(.CO M Mouse NKR-Pl. A Family of Genes Selectively Co-expressed in Adherent Lymphokine-activated Killer Cells. J ~mmrrnol 1991, 147:1X&1708. Thea grcxq’ pre\iously isolated cl>NAs encodmg the rat NKR PI molecule. rhrough which NK cells can he activated (see also [ 13,171 ) cDNA~encoding additional forms of the NKR-PI molecule were cloned from a iihrdv conswucted from mouse NK cells. These forms appcx

on

K: Two Distinct Classes of Carbohydrate-recognition Domains in Animal Lectins. .I Hid C’xm 1988, 263:955”9560.

killer

22. ..

1 IISEROUI

JC, TKUCCO M: NKR-Pl, a Signal Transduction Molecule Natural Killer Cells. Scirrzcr 1990. 249:129~1301.

on natural

Gene Complex on Mouse Chromosome 6. ,J Immunol 1991, 147:3229-3236. This study demonstrates that Ly 49 and the murine form of the rat NKR~ PI molecule are structurally similar and encoded by distinct genes. These molecules are srlecti\~ely expressed by NK cells as type II integral membrane, disullide-linked homodimers and are homologous to the Ca~+~dependent lectm superhmily. Moreover, the genes encoding these molecules are gene6caUy Linked in a chromosomal region termed the UKC.

HISIXODT

JC: MonoclonaJ Antibody to a Triggering Structure Expressed on Rat Natural Killer Cells and Adherent Lymphokine-activated Wer Cells .J Exp Mxl 1989, 169:1373-1389.

structures

YOKOYAMA

R: Demonstration by Class I Gene Transfer that Reduced Susceptibility of Human Cells to Natural Killer Cell-mediated Lysis is Inversely Correlated with HLA Class I Anti&-n Expression. EuvJ Imnzunol1989, 19:447-451.

H-2Kb Antigen

Expression

I, 11ooi~

I., OS~KAV~ROSENIU%C

has no Effect on Natural

S,

Killer

72

Innate

immunity

Susceptibility and Tumorigenicity Itnmunol 1988, 141:4403-4309. 34.

35.

.I

-r5

KARRF

tibility to Natural Wer Cell-mediated Cytolysis is Independent of the Level of Target Cell Class I HLA Expression. .I lrnmttno[ 1989, 142.214&2147.

-16

YOKOYA~~AWM, KEHN PJ, COHEN

f?.

YOKO\~ZMA

LElDEN JM, &wNSKl

IsA. GoTTSCHALK

of a Murine

Hepatoma.

I., KORNBLIITH

J: SUS‘xp

NJ, UST WM, VoORIx)liX’ AC, PASTOOR LB, VAN DER HOEVEN FA, MEuEF CJM, PIOEGH HI.: Lack of Correlation STAM

Between Levels of MHC Class I Antigen and Susceptibfiity to Lysis of Small Cellular Lung Carcinoma (SCLC) by Natural Killer Cells. .I Immuno( 1989, 142~4113-4117. 36.

STORKLIS WJ, AIEXANDER J, PAXVE JA, CRESSWEI.I. P. DAWSOY JR: The al/a2 Domains of Class I HLA Molecules Confer Resistance to Natural Killing. .I I?nmunol 1989, 143:3853%3857.

Btx M, IJAO N-S, ZIJIS’IXAM, IIXING J, J~ENISCHK, R~cIE’I’ D: .. Rejection of Class 1 MHC-deficient Haemopoietic Cells by Irradiated MHC-matched Mice. ,Vature 1991, 349.323-331. This, together with [38**,39**], examines NK cell function in trans~ genie mice with a selective mutation (by homologous recombination) in the P2-microglobulin gene. These mice do not express MI IC class I molecules normally. Surprisingly, hematopoietic stem cells from these mice were rejected by irradiated normal mice that were otherwise MHC~ matched. This rejection was mediated by NK1.1 + cells. This resembles the phenomenon of hybrid resistance [40] where host NK cells in Fl hybrid mice reIect parental bone marrow grafts. LIAO N-S, BIX M, ZIJISTRAM, JAI’NISCII R, RALIIETD: MHC Class I Deficiency: Susceptibility to Natural Wer (NK) Cells and Impaired NK Activity. Scierzcc 1991, 253:19’+202. In contrast to cells from normal mice, cells from j3Z-microglohulin~de~ licient mice were susceptible to lysis by NK cells. NK cells from the mutant mice displayed significantly less cytolytic activity against tumor targets. 39. ..

P, OHLEN C, CARBONE E, FRANKSSONL, LJLJNCCREN IAT~~JR A, KOI.I.FRB, KARRE K: Recognition of Beta 2-

HOGLIIND

HC,

microglobulinNegative (Beta 2m-) T-cell Blasts by Natural Killer Cells from Normal but Not from Beta 2m- Mice: Nonresponsiveness Controlled by Beta 2m- Bone Marrow in Chimeric Mice. Proc Null Acad Sci USA 1991, 88:10332-10336. An independent study reporting findings similar to [37**,38**]. In addition, NK cells from pz-microglobulin~delicient mice were unable to lyse syngeneic targets. Taken together, these studies provide compelling Eve dence supporting the in zjitroohservdtions that target cell susceptihilit) to NK cells is inversely correlated with target cell MHC class I expres sion. 40.

BENNE’IT,

Immunol

M: Biology and Genetics 1987, 41:333445.

REMRECKI RM,

K~IMAR V,

of Hybrid

Resistance.

Ad{,

DA\TI> CS,

41.

BENNU”r M: Bone Marrow Cell Transplants Involving Intra-H-2 Recombinant Inbred Mouse Strains. Evidence that Hemopoietic Histocompatibility-1 (Hh-1) Genes are Distinct from H-2D or H-2L. J lmmunol 1988, 141:2253-2260.

42.

OHIEN C, KUNC G, HOGI.LIND P, HANSSON M, SCANGOS G, KARRE K: Prevention of AIlogeneic Marrow Graft Rejection by H-2 Transgene in Donor Science 1989, 246:666668.

RIEBE~UCH C, JAY G,

Bone Mice.

WJ, SALTER RD, AIEXANUEHJ, WAKU FE, Rtllz KE. CRESSQXLLP, DAWS~N JR: Class I-induced Resistance to Natural Wing: Identification of Nonpermissive Residues in HLA-AZ. Prcu Natl Awd Sci USA 1991, 88:598%5992. A systematic study, together with [26,361, of the domains of MHC class I molecules involved in target cell resistance to human natural killing, culminating in the identification of a single residue in a side pocket of the peptide-binding groove that influences ability of MIIC class I molecules to confer resistance. These studies strongly suggest that MHC class I molecules may present peptides to NK cells as well as to T cells.

43. ..

44.

STORKLIS

BJORKAUNPJ, PARHAM P: Structure, of Class I Major Histocompatibility Rio&em 1990, 59:253-288.

Function, and Diversity Molecules. AWZ KeI’

DI, SHEVACHEM: Chromosoma1 Location of the Ly-49 (Al, YE1/48) Multigene Family. Genetic Association with the NKI.1 Antigen. ,I 1~zmrcnol 1990. 14532353%2358.

WM, JACOBS I& KANAGAK’A 0, SHEVACH EM, COHEN I: A Murine T Lymphocyte Antigen Belongs to a Supergene Family of Type II Integral Membrane Proteins. ./ ~~nnz~no/ 1989. 143:1379-1386. D

48.

37.

38. ..

K: Role of Target Histocompatibility Antigens in Regulation of Natural Wer Activity: A Reevaluation and a Hypothesis. In .Mechani.vn.s of‘Qtotosici& @)I,VK Cells Edited by Herheman Ku, Callewlert DM. Orlando: Acddemlc Press; 1985:81-92.

CHAN P-Y. TAKEI 1’: Molecular Cloning and Characterization of a Novel Murine T Cell Surface Antigen, YE1/48. .I frrzm~nol 1989, 142.1727 1736.

S, FKEI;MAN JD, KFLIXHEK C, ,MAGEK D, TAI(EI F: Ly-49 Multigene Family. New Members of a Superfamily of Type II Membrane Proteins with Lectin-like Domains. ./ Immzrr~ol 1991, 147:l-t17-1+23. cDNA\ encoding additional forms of Ly-49 were cloned from an Fl hybrid mouse lihraq. These may represent polymorphism w&n an individual or all&c polymorphism of Ly-49.

-+9. .

WONG

KAIUOFEK FM, F~HAIIDO IK, YOKOYAMA WM: MHC Class I AlNatural Killer loantigen Specificity of Ly-49 + IL-2.activated Cells. Nature 1992, 358:66X The murine Ly--t9 molecule is expresstul by a distinct subpopulation of NK cells. IL-Z-activated NK cells expressing Ly~49 were equivalent to other NK cells in cell surface expression of other molecules and qtolytic potential. However, Ly~+9 ’ + NK cells could not kill rargets ex pressmg certain MHC class I molecules. Trdnsfection of a susceptible target with a cI)NA encoding the H-2DCi class I molecule conferred pref erential resistance to Ly~49+ NK cells. This resistance was reversed with mAhs directed against Iy-49 or ctIUct2 domains of H~2fl. Thus, Ly 49 was proposed to he an I% cell surface molecule that engages specific MIIC class I molecules on target cells and that delivers inhihitoty signals to the NK cell. 50. ..

51. .

GOFER

FM, KII~ALT~, RK, YOKO~~LMAMM: The Interaction of Ly-49 with H-2Dd Globally Inactivates NK Cell Cytolytic Activity I’txns Asoc Anrer Pkqaiciuxs 1993, in press. The apparent engagement of the MHC class I molecule, H~2Dd, on the target cell by Ly-49 on the NK cell globally affects ability to stimulate NK cells through other mechanisms such as antibody-dependent cellu~ lar cytotoxicity This is consistent aqth the possibility that Ly~49 is an inhibitory NK~cell receptor.

i2.

CICCONE

E,

PKNIx!

D,

vWli

0,

nl

DO&AT0

C,

.rKII’OUI

G,

A, MO~UXTAL. Evidence of a Natural Killer (NK) Cell Repertoire for (Allo) Antigen Recognition: Definition of Five Distinct NK-determined AlIospecilicities in HumnS. J kp Med 1992, 175:709-718. The NKG2 cDNA clones may encode human homologs of molecules encoded in the mouse NKC (see also [21**] ) because the putative polypeptides resemble the rodent NK-cell molecules, NKR~Pl and Ly49. All molecules appear to he selectively expressed by NK cells as ape II integral membrane proteins with homology to the Ca* + ~dependent lectin superfamily. .

OWNGO

53.

SLKLKI

AM,

GLIAIUX~IA

BLANCHI E. BASK H, SllZliKl T, BENDERJ. PARDI K, CA, LARRICKJW, ENGIEIL~ANEG: Natural Killer Lines

N,

I~NNER

and Clones with 1990, 172:457462. jr.

55. .

J. MO~TTA

Apparent

Antigen

Specificity.

J Exp Med

CICCUNE E, C~L~NNA M, VLU 0, PENUE D, DI DONATO C, REINHARZ D, AMOROSO A, JEANNET IM, GIIARDI~IA J, MORI?I-I’A A, ET AL.: Susceptibility or Resistance to Lysis by Alloreactive Natural Wer Cells is Governed by a Gene in the Human Major Histocompatibility Complex Between BF and HLA-B. Proc Null Acad Sci USA 1990, 87~9794~9797, and (erratum) Proc Nutl Acad Sci lJSA 1991, 88~5477. IIOUCHINS

Analysis

JP, YABE T, MCSHERRYC, BACII FH: DNA Sequence of NKG2, a Family of Related cDNA Clones Encod-

Recoenition

ing Type II Integral Membrane Proteins on Human Natural K&r Cells J Ex[, Med 1991, 173:1017-1020. The NKG2 cDNA clones may encode human homologs of molecules encoded in the mouse NKC (see also [ 21**]) because the putative polyppeptides resemble the rodent NK-cell molecules, NKR~Pl and Ly49. All molecules appear to be selectively expressed hy NK cells as type 11 integral membrane proteins with homology to the Cal+ -dependent lectin superfamily. 56

SCAIZO AA, FITXEI?ALLI NA. S~xrxious A, IA VISTA AR, SHEI&\{ GR: Cmv-I, a Genetic Locus that Controls Murine Cytomegalovirus Replication in the Spleen. ./ fi.q ,Zfed 1990, 171.1469-1483. WFLYH RM,

5x

%MNIEY

59 ..

JD: In Viva Administration of Monoclonal Antibody to the NKl.1 Antigen of Natural Killer Cells: Effect on Acute Murine Cytomegalovirus Infection. ,/ Med Viral 1990, 30.5%60. Scrwo

AA,

FITZGERAIII NA,

WALWCE

CR,

GIHBON~

AE,

on natural

killer

cells Yokovama

A single autosomal dominant locus, Clmcl-I, which IS linked to the mouse NKC (see also [21**]), controls susceptibility to MCMV infection The locus appears to mediate its effect through NK cells. 60.

MOWITA A. TAMHISSI G, BOTTINO C, TRIPODI G, MIXLI A, CICCONE E, PK~AIEO G, MORETTA L: A Novel Surface

Antigen Expressed by a Subset of Human CDS- CD16+ Natural Wer Cells. Role in CeU Activation and Regulation of Cytolytic Function. .I Exp 12Ted 1990, 171:695-714. 61.

DI:UIX)N PL, Eyxm IX, I~RIIHAKER JO, Koo GC. O’IXXVNLLLCL: Demonstration of the Antiviral Role of Natural Killer Cells in Vim With a Natural Killer Cell-specific Monoclonal Antibody (NK 1.1 ). Nnl Immzrn C.B/l GrowthKeg rtlat 1990, 9:112~120.

57

structures

MOKEII’A A, IW~~INO C. PENIIE D, TKIPODI G, TAMH~ISSI G, VIALE 0. ORI:ILGO A, HARBAKESIM, MI’RLI A, CICCONE E. MORETTA L: Identification of Four Subsets of Human

CD3CD16+ 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. .f ,‘z.x~ .I/ltd 1990, 172:1583-1598. 62.

SENTMAN

CL, HACKETTJ JR, K~WAKV, BENYF’I”I’ M: Identilication of a Subset of Murine Natural Wer Cells that Mediates Rejection of Hb-ld but Not Hb-lb Bone Marrow Grafts. ,/ ,?.q~ .~Ix/ 1989, 170:191&202.

SMART

GR: The Effect of the Cmv-1 Resistance Gene, Which is Linked to the NaturaI Killer CeU Gene Complex, is Mediated by Natural Killer Cells. J Itn nzwol 1992, 149:581-589.

YC, BURTON KC, SHEUW

WV Yokoydmd. Departmenr of Medicine and Brookdale Center for Molecular Biology, Box 1126, Mount Sinai Medical Center, One Gw tave I.. Ir\y Plxe, New York. New York 10029, LISA.

73