Are TCRαβ cells and TCRγδ cells that different?

606

33 "a F O R U M I N I M M U N O L O G Y

1TOHARA,S., FARR,A.G., LAFAILLE,J.J., BONNEVILLE,M., TAKAGAKI,Y., HAAS,W. d~.TONEGAWA, S. (1990), Homing of a ~"~ thymocyte subset with homogenous T-cell receptors to mucosal epithelia. Nature (Lond.), 343, 754-757. JANEWAV,C.A. Jr, JONES,B. & HAYDAY,A.C. (1988), Specificity and function of T cells bearing y/~ receptors. Immunol. Today, 9, 73-76. JAMS, E.M., KAUFMAN,S.H.E., SCHWARTZ,R.H. & PARDOLL,D.M. (1989), Activation of "t'/~ T cells in the primary immune response to Mycobacterium ;uberculosis. Science, 244, 713-716. KYES,S., CAREW,E., CARDING,S.R., JANEWAY,C.A. Jr. & HAVDAY,A.C. (1989), Diversity of T-cell receptor y-gene usage in intestinal epithelium. Proc. nat. Acad. Sci. (Wash.), 86, 5527-5531. Lv VRaNCOIS,L. & GOODMAN,T. (1989), In vivo modulation of cytolytic activity and Thy.l expression in TCR-~,/~+ intraepithelial lymphocytes. Science, 243, 1716-1718. MODLIN, R.L., PIRMEZ, C., HOFMAN, F.M., TORIGIAN, V., UYEMURA,K., REA, T.H., BLOOM, B.R. & BRENNER,M.B. (1989), Lymphocytes bearing antigen-specific ~/B T cell receptors accumulate in human infectious disease lesions. Nature (Land.), 339, 544-548. RAJASEI
ARE TCRa~ CELLS AND TCR~,~ CELLS THAT DIFFERENT? J.A. Bluestone (i) and L.A. Matis (2) O) University o f Chicago, Chicago, IL, and (2) Division o f Cytokines, Food and Drug Administration, Bethesda, M D (USA)

It has been fashionable over the past several years to consider TCRa[3 and TCR-t'~ cells quite distinct in terms of their repertoire and possible physiologic function. The selective tissue localization of some subsets of TCR~B cells (Allison et al., 1988; Tonegawa et aL, 1989; Goodman and Lefrancois, 1988; Bucy et aL, 1988 ; Havran et al., 1989), as well as the relatively restricted T-cell receptor usage in those tissues suggest a possible role of this specialized T-cell subset in recognizing non-polymorphic MHC or conserved antigens (Asarnow et al., 1988). In fact, the identification. of bacterial antigens (Janis et al., 1989; Kabelitz et al., 1990), more specifically

heat shock proteins (Born et al., 1990; Holoshitz et aL, 1989), as potential ligands for TCR'r~ cells has solidified the notion that these cells may indeed play a unique role in the immune system. In this brief review, we would like to summarize our data with regard to the potential diversity of splenic and l y m p h - n o d e - d e r i v e d TCRyB cells (termed "circulating" throughout the review) and compare the general observations of ligand specificity for these cells and those of TCRa[3 cells. Finally, we will discuss the possibility that these two subsets are not functionally distinct but reveal phylogenetic and lineagespecific evolution.

~

T CELLS

Early in 1987, we set out to determine if TCRy~ cells were capable of recogmzmg MHC proteins. In those studies, we derived a TCRy~ cell, G8, from a BALB/c (H-2d) nu/nu mouse specific for an allogeneic class I gene product encoded in the TL region of the H-2 k and H-2d MHC (Matis et al., 1987; Bluestone et al., 1988; Bonneville et al., 1989). It was determined that the G8 TCR~.~ expressed a V~'2-C-rl (*) chain in association with a ~ chain composed of a V0cl I variable gent element. Subsequently, other laboratories identified cells specific for Qa-I (Vidovic et al., 1989) and human CDlc (Porcelli et aL, 1989). In fact, a thymus-derived autoreactive TCRTB hybridoma sharing a similar, or possibly identical, specificity as the G8 clone was derived by Tonegawa and his colleagues (Ito et al., 1990). This led us and others (Janeway et al., 1988) to hypothesize that TCRyB cells recognize conserved MHC class I proteins. This hypothesis fit nicely with the notion that the TCR~,B population had a more restricted and limited repertoire than the TCR0t[3 counterparts especially in light of the limited number of V'r and V8 gene elements identified. In fact, an exciting and novel possibility has been suggested that TCRTB cells and non-classical MHC class I mole~ u l . ~ , . , a ILICLV~

'~,OUV'~lV~.,IdL tO

ICUI.,P~II

Lq~ t i l e

conserved set of endogenous and foreign determinants" (Ito et al., 1990). However, over the past two years, we have begun to question whether TCR-I'8 cells have a specialized repertoire. Of the many alloreactive TCR'r~ cells, we have generated, all have been shown to recognize classical class I and class II MHC molecules (Bluestone et al., 1988; Matis et al., 1989), rather than the non-polymorphic class-l-like MHC molecules. In fact, we have been routinely unsuccessful in generating additional TL-specific TCRy8 cells. The relative ease in generating "classical" alloreactive T C R ~ cells has been confirmed and extended in other species including man and sheep, and suggests that the MHC-specific repertoire of

(*) Nomenclature B (see Appendix).

607

TCRy~ cells may be far more diverse than previously appreciated (Ciccone et al., 1988; Paliard et al., 1989; Rivas et al., 1989). One approach towards examining the potential diversity of the TCR-¢8 repertoire has been an examination of the diversity of the ~ and "t chains expressed on lymph node and splenic TCR'r~ cells. Although TCRy~ ceils selectively localized in epithelial tissues have restricted" r and ~ gene segment usage (Asarnow et al., 1988; Tonegawa et al., 1989) and, in some instances, express a highly conserved TCR~, and VDJ junctional sequence, the circulating TCR'r~ cells express a quite diverse potential repertoire (Cron et al., 1989a,b; Cron et al., 1990; Ezquerra et al., 1990). First of all, at least three distinct y chains are utilised on splenic TCR78 cells including the predominant thym]c "I" chain, V~2-C-rl, Vyl.l-Cy4 and Vy1.2-C-¢2. Also, at least seven V8 chains have been identified on splenic TCR'r~ cells. Finally, junctional nucleotide analysis of splenic and lymph node TCR'r8 cells has shown an extensive diversity unmatched in any of the epithelial tissues studied. In some instances, both D regions and as many as three N regions have been identified to create an extremely diverse junctional sequence. The potential for the extensive diversity, especially at the junction, has recently been shown to have implications in the MHC-specific repertoire of these cells. Our laboratories have derived two distinct TCR-t'8 clones, one specific for I-E k and the other specific for I-Ad. Although both express the identical V~, (Vy1.2) and V8 (V~5, the most predominant VS) chains, the junctional sequences are totally different. Interestingly, the 7 chain used in these clones was derived from the V~-l.l-J-t.2 rearrangement, a gene combination that is expressed in small amounts throughout ontogeny and in the adult thymus and is maintained as a minor subset within the circulating ~ pool in the lymphoid system. Taken as a whole, these results would suggest a considerable

608

33 ''d F O R U M

IN IMMUNOLOG

potential for diversity within the TCR~,8 repertoire. In fact, the limited diversity seen in peripheral epithelial tissues may reflect a positive selection of a diverse population of TCR-f~ cells due to antigenic exposure in those tissues (Lafaille ct ai., 1990). What about the recognition of bacterial proteins in an MHC-unrestricted manner? There is growing literature that suggests that TCR-f~ cells are capable of recognizing a variety of bacterial antigens including staphylococcal enterotoxins (Rust et al., 1990), mycobacterial proteins (Janis et al., 1989; Kabelitz et ai., 1990), a variety of heat shock proteins (HSP) (Born et al., 1990; Holoshitz et al., 1989) and other stressrelated molecules (Rajasekar et al., 1990). This has led to the suggestion that these T cells may be selectively skewed towards recognizing these antigens in an MHC-unrestricted manner. Several important questions have been raised by these studies. First of all, does the recognition of these molecules reflect a nominal specificity or a "superantigen" specificity (Kappler et al., 1989)? Although there is limited V region usage by cells recognizing specific bacterial antigen, there is extensive junctional diversity in these clones. For ins~,~,,,.~, m the case of some of the HSP65-specific cells (Born et al., 1990), both the TCR-( and TCR~ chains, preferentially utdizing V~'I.I-C'r4 and V~6-C8, respectively, have extensive diversity in their V(D)J junctions. Similarly, the HSP-reactive V-r9-V82 expressing peripheral "r~ T cells also have this extensive junctional diversity (Parker et al., 1990). When taken together, these results are not so dissimilar from what has been observed in TCR0t~ cells. The capacity of TCRe~[3cells to recognize foreign proteins in the context of both class I and class II MHC antigens is very much dependent on the junction of the variable and joining regions. Yet, these T cells also have the capability of recognizing bacterial "superantigens", i.e. staphylococcal enterotoxins, based predominantly on variable region gene segment usage and not junctional diversity (White et al., 1989). Finally, although these proteins bind to MHC

Y

molecules, the T-cell receptors do not recognize the MHC molecules, suggesting that antigen recognition is MHCunrestricted. One criticism of the possibility that ~,Bcells have an MHC-specific repertoire has beeil the difficulty in routinely generating alloreactive TCR'rB cells. However, one cannot underestimate the primitive nature of our understanding of the growth conditions for this cell population. The possibility of distinct lymphokines and other secondary signalling structures on accessory cells that may be necessary for triggering these cells must not be underestimated. For example, the ability of human TCR~,~ cells to recognize staphylococcal enterotoxin can be shown by activation of lytic activity, not proliferation (Rust et al., 1990). In addition, the relative success in generating MHC-specific ~8 cells in other species such as sheep, pig and man has not been fully appreciated. It therefore seems possible that the TCRyB and ~[3 repertoires are not so different in the capability of T cells to have two rather distinct overlapping repertoires. One TCR repertoire may be for bacterial antigens and may represent a primitive recognition system for both of these cell populations that has been conserved throughout phylogeny. By comparison, the peptide-specific MHCrestricted T-cell repertoire may be an evolutionarily more recent adaptation for specific immune recognition. Thus, both TCR'r8 and TCRa[3 cells may have travelled the same evolutionary pathway, with 0t[3cells evolved to recognize a more diverse MHC-specific repertoire. This occurred while their ability to recognize "non-MHC-restricted superantigens" such as staphylococcal entero',oxins or HSP was conserved. Likewise, two functional specificities evolved within the TCR-r~ population. Those non-circulating TCR~8 cells which reside in epithelial tissues may have evolved less diverse TCR ~ and usages skewed towards the recognition of relatively conserved MHC proteins or more likely stress-related and bacterial antigens. In contrast, the circulating population of TCR'I,~ cells may be more like TCRat[3 cells in that they recognize

609

"y8 T C E L L S

"superantigens" as well as a more specific MHC-restricted repertoire. One piece of evidence for these distinct lineages of TCR'r8 cells is seen in man, where the TCR-f8 cells generated against alloreactive cells often use the VS1 gene element (Rivas et al., 1989), whereas the bacterial antigen-specific human TCR~'~ cells use V82 (Fisch et al., personal communication). There is no doubt that the two distinct types of recognition by both

TCRa[3 and -'r8 cells are likely to be critical and important in the immune response. The i m m u n e system must necessarily evolve to be able to recognize c o m m o n foreign antigens which may be quite similar and highly conserved yet retain the specificity necessary to distinguish self from non-self. It therefore remains the challenge of T-cell immunologists to determine the rules which govern this repertoire development.

References.

ALLISON,J.P., HAVRAN,W.L., ASARNOW,D., TIGELAAR,R.E., TUCKER,P.W. & BONYHADI,M. (1988), Gamma delta antigen receptors of Thy-l ÷ dendritic epidermal cells: implications for thymic differentiation. Immunol. Res., 7, 292-302. ASARNOW,D.M., KUZIEL,W.A., BONYHADI,M., TIGELAAR,R.E., TUCKER,P.W. & ALLISON,J.P. (1988), Limited diversity of gamma delta antigen receptor genes of Thy-I ÷ dendritic epidermal cells. Cell, 55, 837-847. BLUESTONE,J.A., CRON, R.Q., CO~ERMAN,M., HOULDEN,B.A. & MATIS,L.A. (1988), Structure and specificity of T-cell receptor gamma/delta on major histocompatibility complex antigen-specific CD3 *, CD4-, CD8 - T lymphocytes. J. exp. Med., 168, 1899-1916. BONNEVILLE,M., ITO, K., KRECKO,E.G., ITOHARA,S., KAPPES,D., ISHIDA,1., KANAGAWA,O., JANEWAY,C.A., MURPhy, D.B. & TONEGAWA,S. (1989), Recognition of a self major histocompatibility complex TL region product hy gamma delta T-cell receptors. Proc. nat. Acad. Sci. (Wash.), 86, 5928-5932. BORN, W., HALL, L., DALLAS,A., BOYMEL,J., SHINNICK,T., YOUNG,D., BRENNAN,P. & O'BRIEN, R. (1990), Recognition of a peptide antigen by heat-shock-reactive gamma delta T lymphocytes. Science, 249, 67-69. Buoy, R.P., CHEN,C.L., CroAK, J., LOSCH,O. & LOOPER; M.D. (1988), Avian T cells expressing gamma delta receptors localize in the splenic sinusoids and the intestinal epithelium. J. ImmunoL, 141, 2200-2205. CICCONE,E., VIALE,O., PENDE,D., MALNATI,M., BATTISTA~ERRARA,G., BAROCCI,S., MORET TA, A. & MORETr.A,L. (1988), Antigen recognition by human T-cell receptor gammapositive lymphocytes. Specific lysis of allogeneic cells after activation in mixed lymphocyte culture. J. exp. Med., 167, 1517-1522. CRON, R.Q., GAJEWSKI,T.F., SnARROW,S.O., FITCH, F.W., MATIS, L.A. & BLUESTONE,J.A. (1989a), Phenotypic and functional analysis of murine CD3 + , CD4-, CDS- TCR gamma-delta-expressing peripheral T cells. J. Immunol., 142, 3754-3762. CRON, R.Q., EZQUERRA,A., COLICAN,J.E., HOULDEN,B.A., BLUESTONE,J.A. & MALOV,W.L. (1989b), Identification of distinct T-cell receptor (TCR)-gamma delta heterodimers using an anti-TCR-gamma variable region serum. J. hnmunoL, 143, 3769-3775. CRON, R.Q., COOl,AN, J.E. & BLUESTONE,J.A. (1990), Polymorphisms and diversity of T-cell receptor-gamma proteins expressed in mouse spleen, hnmunogenetics, 31,220-228. EZQUERRA,A., CRON, R.Q., McCONNELL,T.J., VALAS,R.B., BLUESTONE,J.A. & COLIGAN,J.E. (1990), T-cell receptor delta gene expression and diversity in the mouse spleen. J. Immunol., 145 (in press). GOODMAN,T. & LEFRANCOIS,L. (1988), Expression of the gamma-delta T-cell receptor on intestinal CD8 + intraepithelial iymphocytes. Nature (Lond.), 333, 855-858. HOLOSHITZ, J., KONING,F., COLIGAN,J.E., DE BRUYN,J. & STROBER,S. (1989), Isolation of CD4- CD8- mycobacteria-reactive T-lymphocyte clones from rheumatoid arthritis synovial fluid. Nature (Lond.), 339, 226-229. HAVRAN, W.L., GRELL, S., DUWE, G., KIMURA, J., WII.SON, A., KRUISBEEK, A.M., O'BRIEN, R.L., BORN,W., TIGELAAR,R.E. & ALLISON,J.P. (1989), Limited diversity of T-cell receptor gamma chain expresston of murme Thy- dendritic epidermal cells revealed by V gamma-3-specific monoclonal antibody. Proc. nat. Acad. Sci. (Wash.), 86, 4185-4189. •

•

•

1+

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lTo, K., VAN KAER, L., BONNEVILLE,M., Hsu, S., MURPHY,D.B. & TONEGAWA, S. (1990), Recognition of the product of a novel MHC TL region gene (27 b) by a mouse "r~ T-cell receptor. Cell, 62, 549-561. JANEWAV,C.A., JONES,B. & HAYDAY,A. (1988), Specificity and function of T cells bearing T~ receptors. Immunoi. Toduy, 9, 73-77. JANIS,E.M., KAUFMANN,S.H., SCHWARTZ,R.H. & PARDOLL,D.M. (1989), Activation of gamma delta T cells in the primary immune response to Mycobacterium tuberculosis. Science, 244, 713-716. K~,BELITZ,D., BENDER,A., SCHONDELMAIER,S., SCHOEL,B. & KAUFMANN,S.H.E. (1990), A large fraction of human peripheral blood T/8 + T cells is activated by Mycobacterium tuberculosis but not by its 65-kD heat shock protein. J. exp. Med., 171, 667-679.

KAPPLER, J.'}~/., PULLEN, A., CALLAHAN, J., CHOI, Y., HERMAN, A., WHITE, J., POTTS, W., WAKEUAND,E. & MARRACK,P. (1989), Consequences of self and foreign superantigen interaction with specific V beta elements of the murine TCR alpha beta. Cold. Spr. Harb. Symp. quant. Biol., 54, 401-407. LAEa!LLE,J.J., HAAS,W., COUTINHO,A. & TONEGAWA,S. (1990), Positive selection of gamma-8 T cells, hnmunol. Today, 11, 75-78. MAilS. L.A., CRON, R. & BLUESTONE,J.A. (1987), Major histocompatibility complex-linked specificity of T8 receptor-bearing T lymphocytes. Nature (Lond.), 330, 262-264. MnTis, L.A., FRY, A.M., CroN, R.Q., CoxtErMAn, M.M., DICK, R.F. & BLUESTONE,J.A. (1989), Structure and specificity of a class II MHC alloreactive gamma delta T-cell. receptor heterodimer. Science, 245, 746-749. PALIArD, X., YSSEL, H., BLANCHARD,D., WaXTZ, J.A., DEVRIES, J.E. & SPITS, H. (1989), Antigen-specific and MHC-nonrestricted cytotoxicity of T-cell receptor alpha beta + and gamma delta + human T-cell clones isolated in IL-4. J. Immunol., 143, 452-457. PAR~ER, C.M., Gron, V., BAND, H., PORCELLI,S.A., MoRrrn, C., FABBI, M., GLass, D., STROMINCER,J.L. & BRENNEr, M.B. (1990), Evidence for extrathymic changes in the T-cell receptor gamma/8 repertoire. J. exp. Med., 171, 1597-1612. DORCELLI, S., BRENNER,M.B., GREENSTEIN,J . l . , BALK, S.P., TERHORST,C. • BLEICHER, P.A. (1989), Recognition of cluster of differentiation 1 antigens by human CD4- CD8cvtolytic T lymphocytes. Nature (Lond.), 341,447-450. RAJASEKAR,~x., qwM,G.-K. & Au(;ustin, A. (1990), Self heat shock and gamma8 T-cell reactivity, h o c . nat. Acad. Sci. (Wash.), 87, 1767-1771. RIvAS, A., KOIDE,J., CLEARY, M.L. & ENGLEMAN,E.G. (1989), Evidence for involvement of the gamma, delta T-cell antigen receptor in cytotoxicity mediated by human alloantigen-specific T-cell clones. J. Immunol., 142, 1840-1846. RUST,C.J.2 VERRECK2F...VIETtoR:_H_ &_KONI_NG,F,_(!_990), Specific recognition of staphylococg,tll ~llt~;IUtOXlll /~ oy llUlllilll 1 CCIISoearlng receptors wlm me v gamma 9 region. Nature (Lond.), 346, 572-574. TONmAWA, S., BrRNS, A., BONNEVILLE,M., FARR, A., ISHIDA,I., ITO, K., ItOHARA, S., JANEwaY, C.A. Jr., KANACAWA,O., KATSUKI,M., Kuao, R., LA~AILLE,J., MOMBAErTS,P., Murphy, D., NAKANISHI,N., TAKACAKI,Y., VAN KAER, L. & VERaEEK, S. (1989), Diversity, development, ligands, and probable functions of T8 T cells. Cold Spr. Harb. Symp. quent. Biol., 54, 31-44. WHITE, J., HErman, A., PULLEN,A.M., Kuao, R., KAPPLER,J.W. & MarrAcK, P. (1989), The V beta-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice. Cell, 56, 27-35. VIDovl, C.D., Ro~u, C.M., MCKUNE, K., GUERDER,S., MACKAY,C. & DEMmC, Z. (1989), Qa-l-restricted recognition of foreign antigen by a "t'8 T-cell hybridoma. Nature (Lond.), 340, 646-650.