Inhibitory MHC class I receptors on NK cells and T cells

IMMUNOLOGY

TODAY

Inhibitory MHC class NK cells Phillips

Lewis L. Lanier and Joseph

and

they

DeMars9:

demonstrated

that

human NK cells kill MHC class I-deficient Epstein-Barr

virus

lymphoblastoid

(EBVJ-transformed

B-

cell lines (e.g. the ClR or

721.221 cell lines), but fail to lyse these cell

tempts to generate tumor-specific cytotoxic T lymphocytes (CTLs). In the absence of

lines when transfected

with certain HLA-A

deliberate immunization, lymphocytes from control animals killed certain tumor cell

or -B genes. Moreover, NK cells could dis-

lines, and since this activity was also pres-

ing wild-type HLA-A2 and HLA-A2 with a

ent in athymic mice, a novel cell type was proposed to be responsible for this function.

site-directed mutation at amino acid 74 in the 0~~domain’O. An analysis of NK-cell

NK cells are capable of lysing tumor cells that express allogeneic major histocompat-

clones indicated

ibility complex (MHC) antigens

alleles and demonstrate

criminate between ClR target cells express-

that individual

can recognize multiple

or tumors

that completely lack MHC molecules. Thus, in contrast to the prevailing evidence for MHC restriction of T-cell recognition, NK cells were considered ‘MHC unrestricted’. However, observations by Karre and colleagues’ suggested that NK cells might in fact serve a unique role in the immune system by

in class I recognition”.

clonal diversity These findings pre-

dicted the existence of multiple NK-cell receptors polymorphic

MHC class I determinants

NK cells

HLA-A, -B and -C

that recognize

and ,ransmit an inhibitory

signal to prevent NK cells from killing target cells that express certain HLA alleles.

detecting and eliminating cells that had lost expression of MI-K class I molecules. This clever strategy may represent the first exMurine inhibitory receptors for polymorphic I-i-2

ample of a biological defense against the stealth technology that is used by certain viruses to evade T-cell recognition by disrupting

molecules

MHC synthesis. The concept of surveillance for ‘missing self-MHC’

While studying

was proposed in 1986, but only a decade later are we beginning to understand the molecular mechanisms responsible for this process.

tiation antigen, Yokoyama and colleagues12 observed that Ly-49A+

the distribution

of the murine

Ly-49A differen-

NK cells were unable to kill H-2Dd ar.d H-2Dk tumor cells, whereas

There is an emerging consensus that NK-cell recognition is regu-

Ly-49A- NK cells efficiently lysed these targets. This suggests that

lated by a delicate balance between positive signals that initiate their effector cell function and inhib:tory signals that prevent cy-

interactions between the Ly-49A receptor and its H-2 ligand on the

tolysis. NK cells can be activated ‘oy the interaction of several mem-

direct binding of Ly-49A to H-2Dd molecules, formally proving that

brane receptors (e.g. CD2, CD16, CD69 and NKF-Pl) with their li-

Ly-49A is a receptor for MHC (Refs 13, 14). Ly-49A interacts with

gands or monoclonal antibodies

(mAbs)2-7. At present, there is no

evidence for a unique NK-cell-specific

receptor that is responsible

target cell inactivate the NK cell. Subsequent experiments have shown

the 0~~and (Yedomains of H-2 (Ref. 12) and ligand recognition apparently requires a stable peptide-H-2

complex. Correa and Rauleti5

for initiating the cytolytic response; rather, it is likely that different receptors may be used depending upon the activation state of the

have shown that Ly-49A+ NK cells can r lcognize a diverse array of

NK cell and the availability of the relevant ligands on the target cell. In contrast to the limited understanding of the molecules re-

self-peptides

sponsible for positive signaling in NK cells, the involvement

peptides.

of re-

peptides bound to H-2Dd molecules, but are unable to distinguish from peptides of viral or bacterial origin; thus, NK-ceil

receptors do not necessarily discriminate However,

between self- and foreign-

evidence has been presented

ceptors in negative signaling is well defined: it is now clear that NK

that NK cells may be capable of distinguishing

cells possess receptors for polymorphic

molecules with different bound peptidesi6.

MHC class I molecules on

potential target cells, and these receptors apparently nals that prevent NK-cell-mediated cytotoxicity. Direct evidence for NK-cell recognition

transmit sig-

of MHC class I mol-

ecules was provided by the studies of Storkus et nl.8 and Shimizu 0 ! 996

E serer Scence Ltd 0167-5699196cS15

FEBRUARY

‘IO

1996

to demonstrate

between MHC class I

Ly-49A is one of at least seven closely related genes on mouse chromosome

6 that are preferentially

expressed

by NK cells*7-19.

These genes are memberr of the superfamily of C-type lectins and encode type II membrane proteins 17-i9.Although Ly-49 genes do not

IMMUNOLOGY

rearrange, there is evidence for alternative splicing and alfeiic polymorphism*8a19. mAbs have been generated

against

the Ly-49A,

TODAY

(a) Human KIR

Ly-49C and Ly-49G.2 glycoproteins, and used to demonstrate that these receptors are expressed as disulfide-bonded homodimers on subsets of NK cells20-23.Because the subsets of NK cells expressing

COOH

~58

P70

Ly-49A, Ly-49C and Ly-49G.2 overlap extensively, most NK cells

COOH

must express more than a single Ly-49 gene. Recent studies have indicated that only a single allele of each Ly-49 iocus may be transcribed in a single NK cell 24;however, the molecular mechanisms responsible for the transcriptional regulation of the Ly-49 genes have not been established. Since they are C-type lectins, the Ly-49 receptors may require carbohydrate

COOH

I

I

NH2

NH2

for ligand binding. In support of this notion, fucoidan

(a sulfated polysaccharide) between

I

I COOH

has been shown to inhibit interactions

Ly-49A or Ly-49C receptors

Nevertheless,

and their H-2 ligands2j,26.

Fig.

I. Strzlcturnl fentwes of(n) hunran killer-cell inhibiton/ wce,vtor (KIR)

md 07) mouse L!y-49 receptor

it is unlikely that the Ly-49 receptors discriminate

between different H-2 alleles on the basis of carbohydrate tion alone. Rather, the lectin interactions of Ly-49 to determinants

recogni-

may enhance the binding

of the H-2 polypeptide.

mains3’. Furthermore,

NKBl KIRs can recognize MHC class I heavy

chains that have been mutated to remove the site for N-linked glycosylation, indicating that carbohydrates are not required for receptor function37.

Inhibitory

C receptors for polymorphic

class I

Although the murine Ly-49 receptors demonstrate no structural homology with the human KIRs, there are striking similarities in

molecules

their distribution

In common with murine NK cells, human NK cells also express re-

KIRs are expressed

ceptors for polymorphic

ently transmit an inhibitory signal upon interaction with MHC class I

MHC class I molecules that inhibit killing

of target cells bearing appropriate nated killer-cell inhibitory

alleles. These receptors, desig-

receptors

(KIRs)27 (see Long, Colonna

and Lanier, this issue), are encoded

by a small family of related

genes located on human chromosome Surprisingly,

the KIRs are members

superfamily

and possess no homology

19 at 19q13.4 (Refs 28-32). of the immunoglobulin

and function. In common with Ly-49, the human on overlapping

subsets of NK cells and appar-

on potential target cells. In addition, KIRs and Ly-49 receptors interact with comparable regions of the human and mouse MHC class I heavy chain molecules, recognize MHC complexed

respectively,

and both appear to

with peptide.

(Ig)

to the murine Q-49 genes

The repertoire of inhibitory WC class I receptors and have a molecular mass of about 58 kDa (p58)28,29*33, Genes encoding Ly-49 receptors and KIRs do not :earrange, but are whereas other KIRs contain three Ig-like loops and have a molecular likely to generate a repertoire of receptors by alternative splicing and (Fig. 1). Certain KIRs contain two Ig-like loops in their extracellular

domains

mass of about 70 kDa (~70) 3oB. At present, 13 different cDNAs of

allelic polymorphism.

the KIR family have been reported,

neouslyexpress several inhibitory MHC receptors, which appa-ently

demonstrated

throughout

and differences

the extracellular,

have been

transmembrane

and

An individual

function independently

NK-cell clone may simulta-

of each other upon encountering

their MHC

cytoplasmic domains (Table 1). While many of the KIRs possess an element similar to the immunoreceptor tyrosine-based activation

ligands39. Therefore, the inhibitory MHC class I receptors are distinct from the rearranging T-cell receptors (TCRs), which also interact

motifs (ITAMs) in the cytoplasmic domains, ITAMs are not found in

with MHC-peptide complexes. Only Ly-49 homodimers have been deteckd LinX I*.osv (see above), but there is the possibility of hetero-

ihe cytoplasmic

regions of the Ly-49 receptors (Table 1).

Certain KIRs that contain two Ig-like loops in the extracellular

dimer formation between different Ly-49 isoforms. The KIRs are not

domain are recognized by mAbs GL183 and El36(Table 1). Expression

disulfide bonded and, as yet, there is no formal demonstration

of the GLI83 and EB6 epitopes correlates with the ability of NK-cell

noncovalent associations

of

between the different isoforms.

clones to recognize two groups of HLA-C alleles that differ at two

Paradoxically, Ly-49 receptors and KIRs can be expressed on NK

residues in the (Y,domain of the HLA-C molecule: GL183’ NK cells

cells in hosts that do not appear to express an MHC class I molecule

recognize ‘group 1’ HLA-C alleles, which express Ser at residue 77

capable of interacting with the receptor. For example, C57BL/6 mice express H-2h yet approximately 20% of their NK cells are Ly-49A+, which is incapable of recognizing H-2b ligands”. Similarly,

and Asn at residue 80; and EB6+ NK cells recognize ‘group 2’ alleles, which express Asn at residue 77 and Lys at residue 80 (Refs 35,36) The mAb DX9 reacts with a KIR, previously

called NKBl (Refs 30,

we have observed expression of the NKBl receptor for HLA-Bw4 in

34), which expresses three Ig-like loops in the extracellular domain.

individuals who are homozygous

NKBI KIRs recognize a site on the HLA-B molecule that maps to

unpublished). Moreover, the frequency of Ly-49A i or NKBl + NK cells is not increased in hosts that express a reactive MHC ligand. However, this does not imply that expression Jf the inhibitory

the HLA-Bw4 structural mow7 in a region similar to the site on HLA-C that interacts with the KIRs that contain two Ig-like do-

FEBRUARY

for HLA-Bw6 CJ.Gumperz C[ai.,

1990

IMMUNOLOGY

TODAY

Table 1. Characteristics of inhibitory MHC class 1 receptors

On NK Ce~(s19’22’27’30’3’*35 Representative reactive mAbs

Putative ligands

ITAtWike motif

KIR-cl42 (NKATI)”

HLA-C ‘group 2’

+

EEW

KIR-~147. II

HLA-C ‘group 2

+

EB6

KIR-cl6(NKATZ)

HLA-C ‘group I ’

+

GLl83

KIR-cl43

HLA-C ‘group I ’

+

GL183

cl49 (NKAT5)c

HIA-C ‘group I’

GLl83

cl39

?

NDd

NKB I (KIR-~12)”

HLA-Bw4

+

DX9

NKB I Be

HLA-Bw4

+

DX9

KIR-clI I (NKAT3)

HL%Bw4

+

DX9

KIR-cl5(NKAT4)’

?

+

ND

Ly-49A

H2-Dd, H2-Dk

-

Al

Ly-49B

?

ND

Ly-49c

H_2d.kb.s

SE6

Ly-49D

?

ND

Ly-49E

?

ND

Ly-49F

?

ND

Ly-49G.I g

?

ND

Ly-49G.29

H2-Dd, H2-L“

LGL- I

Ly-49G.3s

?

Receptors Human KIR-related

MouseQ-49

ND

-

Ly-49H ? ND -Abbreviations:Ig, immunoglobulin;ITAM,immunoreceptortyrosine-basedactivationmotif;KIR,killer-cellinhibitoryreceptor;mAb, monoclonalantibody;MHC, major histocompatibilitycomplex; NK, natural killer. WR-~147.11and NKATldiffer by two amino acids in the extracelIuIardomain. bReactivityof NKATlwith EB6has not been directly shown, but is likely. ‘cl49and NKATSdiffer by two amino acids in the leader sequence. ‘ND indicates that none of the existing mAbs is known to react with the protein encoded by the cDNA. ‘NKBIBis identical to NKBIwith the exception of an 18 amino acid deletion between the Q-proximal domain and transmembrane domain, probably resulting from alternative splicing. ‘KU7-cl5and NKAT4differ by one amino acid in the extracellulardomain. h’Ly-49G.1, G.2 and G.3 probably represent splice variants of the same gene. MHC receptors is unaffected by the MHC of the host. In honcmarrow-chimeric mice that express H-2D1’either on donor marrow or host cells, the Ly49A receptors on NK cells are clo~~~nr~gulatcd, presumably as a conscqu~ncc of ligand binding”‘. Similarly, expression and function of the Ly--WA receptor are affected in C37BL/h

11~the observation

tha7tNK ccalls in mice wit-11disrupted

globulin genes arc’unable to kill MHC class I lymplddasts,

How is the repertoire genemed?

cells in normal B6 mice reject transplanted

It can bc assumed

cells”. ‘Education’ of NK cells by self-MHC class I is also suggested

FEBRUARY

I996

whcrca:;

NK cells from syngcneic, wild-type mice efficiently lysc MHC class I I~mphoblast targ&‘.

mice tha! evpress dn H-2Di transgene ” . H-2D”-t-ransgcnic B6 mice < acccpi: allografts fmn- H-3nLi bone marrow donors, ivhcrcas NK H-2D” bone marrow

&-micro-.

inhibitory

that each NK ccl1 must express at least onto

receptor for at least one self-MHC class I molecule irk

IMMUNOLOGY

order to avoid autoimmunity. progenitor

An NK-cell

TZDAY

Bone marrow donor

that fails to express an inhibitory

receptor for a self-MHC class I allele at an appropriate time would presumably fail to differentiate,

whereas

an inhibitory would

interaction

receptor

permit

between

and a self-ligand

development

to proceed.

Expression of inhibitory MHC receptors for MHC alleles that are not present in the host would not be deleterious and therefore may represent a neutral event. To provide for expression of inhibitory MHC receptors

on

the Ly-49 and KIR

subsets of lymphocytes,

genes may be controlled by a stochastic process whereby differentgenes in the family are independently

regulated. Thus, an in-

dividual cell may transcribe one or more of these

genes,

with the only

requirement

being that at least one of the receptors binds to a self-ligand. this would potentially

enable the F, host to reject bone marrow

lmpIicarions

grafts from either parent, but not syngeneic F, marrow. Consistent with this model, Sentman ct d.4’ have implicated Ly-49C- NK cells

If the repertoire of inhibitory MHC class I receptors does function

in the rejection of Hh-incomuatib!?

in this manner, what are the implications in an outbred population of a species with several MHC class I genes? For example, humans

be noted that Hh resistance only prevents engraftment of hematopoietic tissues, whereas parental skin and organ transplants

have three polymorphic MHC class I genes (HLA-A, -B and -C) and most normal tissues co-dominantly express the gene products of all

are readily tolerated in F, hosts. The antigens recognized by NK cells that initiate the cytolytic responses may be preferentially ex-

loci (i.e. potentially six different MHC class I ligands). If a stochastic process regulates expression of the inhibitory MHC receptors, at

pressed by hematopoietic tissues; other tissues may be ignored by the host NK cells because the!. lack an appropriate stimulus.

bone marrow grafts. It should

least some of the NK cells in a host may express only a single receptor for one of the six available ligands. This would be advantaC receptors for MMC class I on T cells

geous in that alteration or loss of a single MHC molecule in a cell would be sufficient for an NK cell to recognize and eliminate the abnormal

cell. This would provide

mechanism potentially

a more sensitive surveillance

than a system that required

tion or transformation.

or loss of of infec-

This may also explain why these receptors

have evolved to recognize polymorphic, determinants

modification

six different MHC molecules as a consequence

rather than monomorphic,

on the MHC molecules. In addition, if allelic isoforms

of the Ly-49 receptors recognize distinct H-2 ligands, this would also provide a rationale for the expression of only a single allele of

is often considered

to be an NK-cell receptor, it

was in fact discovered on T cellsJ”,J7and is expressed on a minor subset of thymocytes and peripheral 1 cell@. Similarly, the human ~58 (Refs 49, 50) and NKBl receptor” are also present on T cells. NKBl is not restricted to any particular type of T cell, and the molecule expressed by T cells is indistinguishable NK ~11s~‘. Inleractions

from that present on

bet-deen NKBI on the T cell and an HLA-Bw4 li-

each Ly-49 gene locuP.

gand on an antigen-presenting cell (APC) can inhibit signals transduced through the TCR complex. This was demonstrated by co-

Hybrid histocompatibility

enterotoxin B (SEB) superantigen presented by either the HLA class I721.221 cell line or 721.221 cells transfected with several different

culturing human CD4- or CDS’ T-cell clones with staphylococcal

The existence of inhibitory MHC receptors that are differentially expressed on NK-cell subsets may explain the phenomenon histocompatibility’

of ‘hybrid

(Hh), a process whereby NK cells in F, recipients

reject parental bone marrow grafts from certain mouse strain&“. As

HLA class I genes. SEB presented by class I 721.221 cells activated in killing of the APC, whereas the

the T-cell clones and resulted

presence of HLA-Bw4 molecules on the APC inhibited T-cell stimulation and effector cell function”. Although only a minor subset of

shown in Fig. 2, NK cells in an F, host would on!y need to express

T cells express NKBl, many T-cell clones appear to express other in-

an inhibitory MHC receptor for either parent ‘A’ or parent ‘B’ MHC

hibitory MHC class I receptors for HLA-A, -B and -C, as revealed by

in order to avoid autoimmunity. However, because a subset of NK

functional

cells in the F, would not express anti-‘A’ or anti-3 MHC receptors,

T-cell clone$‘. Furthermore,

analysis

of a panel of randomly generated NKBl northern blot analysis has confirmed

IMMUNOLOGY

TODAY

adhesion molecules (ICAMs), CD28 ligands and CD401. In this case, expression inhibitory

receptor

that

of an

recognizes

self-

peptide-MHC complexes may serve as a fail-safe mechanism to prevent inappropri-

Foreign-peptide-MHC

ate responses and destruction of normal bystander cells at a site of inflammation. Thus, the net result is dictated by a delicate balance between

inhibitory

and stimulatory

signals. The finding that T-cell responses are regulated by stimulatory

and inhibitory

MHC

receptors that bind MHC ligands provides a new conceptual framework for understandFig, 3. A h!ypotheticnlmodel for the regdntiorz of T-cell responses b!ythe T-cell receptor (TCR) ad

inhibitoy mnjor histocompntibility cotnplex (MHCJ clnss 1 receptor follozoing internctiotz zoith nn nntigen-presenting cell (AK). (2) Biding of the TCR to a foreign-peptide-MHC complex initintcs n positive signnl thnt results it1 nctivntiolz of tyrositze kinnses. (2) TCR-nctivnted tyrosine kinnses phosphoylnte tzenrby inhibitory MHC clnss I receptors, zdzich then become functionally active. (3) Activnted inhibitory MHC clnss I receptors inhibit further TCR signal trnusductz’on,possibly by

ing the regulation Although

of an immune response.

the biochemical

rently unknown,

events are cur-

a hypothetical

scheme of

how this might operate is shown in Fig. 3. When an NK or T cell encounters an APC, or other potential target cell, a positive signal is

transmitted via a stimulatory receptor on recruitment of n tyrosine phosphntnsethnt dephosphorylntesmolecules in the TCR signnl trnnsductiolz the NK cell or through the TCR on T cells. pnthzvny(e.g. CD3 5 chain nd ZAP-70) nmf subsequently innctives the inhibitory receptor. This This event immediately activates the inmodel mi,cht also apply to rznturnlkiller 0.Wcell recognition. hibitory receptor, making it functionally competent.

If normal peptide-MHC

com-

the presence of transcripts of the KIR gene family in certain NKBl -

plexes are present on the cell surface of the APC that has initiated

T-cell clonego. NKBl is preferentially

the positive signal, the inhibitory MHC receptor on the responder expressed

on T cells with a memory

cell will transmit a negative signal, serving to dampen the response

phenotype, and is not frequently expressed on either thymocytes or

rapidly by interfering

cord blood T cells (L. Lanier, unpublished). This suggests that inhibitory MHC class I receptors may appear on T cells only after

tory signals (possibly by the recruitment of phosphatases).

Because

APCs or potential target cells will usually simultaneously

express

activation, at which point they are needed to control the extent of an

foreign-peptide-MHC

immune reaction. While the events regulating expression

cell surface, both the stimulatory

inhibitory

MHC receptors

are unknown,

induction

chronic exposure to antigen or the environmental

of these

with, and possibly terminating,

and self-peptide-MHC

the stimula-

complexes on their

and inhibitory

MHC receptors

may require

will be engaged. Therefore, the ultimate response will depend

on

influences that are

the strength of the opposing signals, which may be influenced

by

responsible for the generation of long-lived memory T cells. Short-

the affinity of the TCR (or other stimulatory

term stimulation of naive T cells itz vitro with polyclonal mitogens

cell) and the amount

does not induce expression of the KlRs (L. Lanier, unpublished).

Thus, a sufficiently strong stimulus can overcome the inhibitory sig-

of contribution

receptors on an NK

by costimulatory

receptors.

nals, enabling T cells or NK cells to respond to APCs in appropriate circumstances.

Inhibitory

Reg6dotion of immune responses

nism for peripheral

The presence of TCRs and inhibitory MHC receptors on a T cell provides a mechanism to fine-tune an immune response. What is the

these receptors

advantage

of this system? During differentiation

in the thymus,

MHC receptors

to function properly

disease. Not only can the model be tested experimentally, accounts for several previous observations

deleted by negative selection. However, during this process, thymo-

of inhibitory

cytes are also positively

receptors only operate if the stimulating

for recognition

Therefore, all T cells are potentially

of self-MHC.

autoreactive, but presumably

have low affinity for self-peptide-MHC,

which is insufficient to ac-

and failure of

could result in autoimmune

immature T cells that express a TCR with high affinity for self are selected

may provide a mecha-

tolerance against self-antigens,

MHC receptors.

but it also

relating to the behavior

For example,

the inhibitory

MHC

antigen and the relevant

MHC class I molecule are present on the surface of the same APC or target cell. Normal bystander

cells that express a relevant MHC

tivate a resting T cell. However, in the situation where T cells are strongly stimulated by a foreign antigen, the threshold for activation

class I molecule do not inactivate the T or NK cell. In addition, inactivation of the effector cell via these inhibitory MHC receptors is

may be lower, and these low-affinity TCR interactions with self may be adequate to initiate a response, particularly if the APC expresses

only transient and does not result in anergy. Because NK and T cells

an abundance

MHC class I molecules, inactivation by bystander cells or induction

FEBRUARY

of costimulatory

ligands [e.g. the intercellular

1996

cell

are constantly

surrounded

by normal, healthy tissues expressing

IMMUNOLOGY

of anergy by these inhibitory productive

MHC receptors would be counter-

in an immune surveillance system designed to seek and

TODAY

2287-2295 21 Mason, L.H., Ortaldo, J.R., Young, H.A., Kumar, K., Bennett, M. and

destroy infected or abnormal cells present at a low frequency in the

Anderson, S.K. (1995) 1. Exy. Med. 182,293-304

host.

22 Stoneman, E-R., Bennett, M., An, J. et RI. (1995) I. Ex,v. Mecl. 182,305-314 23 Yokoyama, W.M., Jacobs, L.B., Kanagawa,

O., Shevach, E.M. and

Cohen, D.I. (1989) I. I~nr~om~l. 143,1379-1386 24 Held, W., Roland, J. and Raulet, D.H. (1995) Nnfure 376,355-358

Concluding remarks Following

25 Daniels, B.F., Nakamura,

the cloning of the KIR and Ly-49 genes, substantial

progress wiII undoubtedly be made in elucidating their ligand specificity, transcriptional regulation and signal transduction pathways. The question of whether serve redundant

these two unrelated gene families

or complementary

functions will need to be re-

solved. Finally, recent evidence suggests that glycoproteins

related

Seaman, W.E. (1994) btmrrrify

MC., Rosen, S.D., Yokoyama, W.M. and 1, 785-792

26 Brennan, J., Takei, F., Wong, S. and Mager, D.L. (1995) J. Bid. Chem. 270, 9691-9694 27 Rajagopalan,

S., Winter, C.C., Wagtmann, N. and Long, E.O. (1995)

1. Inzmurrol. 155, 4143-4146 28 Wagtmann, N., Biassoni, R., Cantoni, C. et al. (1995) Imwtunif!y2,439-449

t the* KIRs may stimulate, rather than inhibit, cell responses upon

29 Colonna, M. and Samaridis, J. (1995) Scieme 268,405-408

binding their MHC class I ligands5’, providing yet another puzzle

30 D’Andrea, A., Chang, C., F:allz-Bacon, K., McClanahan, T., Phillips, J.H. and Lanier, L.L. (1995) I. hmrrrrol. 155, 2306-2310

to solve.

31 Wagtmann, N., Raiagopalan, S., Winter, CC., Peruzzi, M. and Long, E.O. Irmrrnify

DNAX Research Institute is supported

by Schering Plough Corporation.

We

thank W. Yokoyama and E. Long for helpful discussions. Lewis Lanier ([email protected]) Resemch Insfifufe

of Molecular

G.R. and Lanier, L.L.

Clrromosowe Res. (in press)

33 Moretta, A., Bottino, C., Pende, D. et al. (1990) I. Ex,u. Ma-l. 172,

md Joseph Phillips me at fhe DNAX and Cehlw

(in press)

32 Baker, E., D’Andrea, A., Phillips, J.H., Sutherland,

Biology, 901 Cdifornin

Avenue, Pdo Alto, CA 94304, USA.

1589-1598 34 Litwin, V., Gumperz, J., Parham, I’., Phillips, J.H. and Lanier, L.L. (1994) 1. E.y. Med. 180,537-543 35 Moretta, A., Vitale, M., Bottino, C.

t’tnl. 11993) 1. El/l.

Med. 178,597-604

36 Colonna, M., Borsellino, G., Falco, M., Ferrara, G.B. and Strominger, J.L.

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1996