2
T ~ T CELLS 677 of ~,/8 T cells both in the thymus and in the periphery. The last point I would like to men- tion is the interesting observation that the -f/8 T-cell system varies considera- bly among species. Whereas ruminants have about half of their circulating T cells composed of the -f/8 subset, humans seem to have lost the very res- tricted pattern of epithelial y/5 T lym- phocytes. The situation of the mouse would be somewhere in-between. C. Mackay and W. Hein have clearly pointed out that different species may to some extent rely on the ~'/8 T cells for their immune defence. In this respect, ethological studies might be of great in- terest in trying to define the precise role of the T/8 T-cell system. References. BONNEVILt.E, M. et aL (1990), Self tolerance to transgenic "r/8 T cells by intrathymic inactiva- tion. Nature (Lond.), 344, 163. CARD,NO,S.R. et aL (1990), Developmentally regulated fetal thymic and extrathymic T-cell receptor "r/8 gene expression. Gene and Development, 4, 1304. GtJY-G~AND, D. et al., Two gut intraepithelial CD8 + lymphocyte population with different T-cell receptor: a role for the gut epithelium in T-cell differentiation. J. exp. Med. (in press). JARRY,A. et ai. (1990), Subsets of CD3 + (T-cell receptor cx/~or "r,/8) and CD3- lymphocytes isolated from normal human gut epithelium display phenotypical features different from their counterparts in peripheral blood. Europ. J. lmmunoi., 20, 1097. H. Spits, H. Yssel and J.E. de Vries: Selection of V~9V82 using TCR'(8 + cells in the human foetal thymus. It is intriguing that the V-f9V82 pair is expressed predominantly in early foe- tal development. As indicated by Trie- bel, it is very well possible that these cells are positively selected in the foetal thymus, although it cannot be formal- ly excluded that cells that rearrange V~9 to J's other than JP or that join V-fl0 or 11 are negatively selected. If the cells are positively selected, the "selecting" antigen is perhaps expressed in the thy- mus only in early foetal development and not after birth, because V~,9V82-positive cells are rare in the postnatal thymus. As indicated by Bol- huis and colleagues, most if not all V'r9V82-expressing cells recognize an antigen on Daudi cells. We have found that foetal TCR3,8 + thymocyte clones expressing V'r9 and V82 respond to Daudi by producing cytokines, but do not lyse Daudi cells. It is suggested that Daudi cells express a 58-kDa stress pro- tein, which may be the target antigen recognized by the V-f9V~2-positive cells. It ma) also be possible that Daudi .ells express the ligand molecule that selects the V~,9V~,2-expressing ..... CellS. It should also be noted that foetal TCR~'8 + thymocyte clones produce sig- nificant levels of IL-4 and IL-5, while postnatal thymocyte clones fail to produce those cytokines (Krangel et aL, 1990, J. exp. Med., 172, 847). IL-4 is known to have profound effects on T-cell growth and probably also on differentiation. It is possible that V-f9V82* foetal thymocytes produce IL-4 in vivo after activation with anti- gens expressed in certain parts of the foetal thymus and thereby influencing growth and/or differentiation of TCR0t[3+ T cells. However, we have yet to demonstrate that foetal V-r9V82 cells produce IL-4 or other cytokines in vivo. One should realize that using the termi- nology "positive selection" does not im- ply that TCR~,8+ are selected in the same way as TCR0~13 ÷ T cells, In a re- cent workshop about TCR'f8 + T cells held in Schloss Elmau, Germany, it was

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Page 1: H. Spits, H. Ysell and J.E. de Vries

T ~ T C E L L S 677

of ~,/8 T cells both in the thymus and in the periphery.

The last point I would like to men- tion is the interesting observation that the -f/8 T-cell system varies considera- bly among species. Whereas ruminants have about half of their circulating T cells composed of the -f/8 subset, humans seem to have lost the very res-

tricted pattern of epithelial y/5 T lym- phocytes. The situation of the mouse would be somewhere in-between. C. Mackay and W. Hein have clearly pointed out that different species may to some extent rely on the ~'/8 T cells for their immune defence. In this respect, ethological studies might be of great in- terest in trying to define the precise role of the T/8 T-cell system.

References.

BONNEVILt.E, M. et aL (1990), Self tolerance to transgenic "r/8 T cells by intrathymic inactiva- tion. Nature (Lond.), 344, 163.

CARD,NO, S.R. et aL (1990), Developmentally regulated fetal thymic and extrathymic T-cell receptor "r/8 gene expression. Gene and Development, 4, 1304.

GtJY-G~AND, D. et al., Two gut intraepithelial CD8 + lymphocyte population with different T-cell receptor: a role for the gut epithelium in T-cell differentiation. J. exp. Med. (in press).

JARRY, A. et ai. (1990), Subsets of CD3 + (T-cell receptor cx/~ or "r,/8) and CD3- lymphocytes isolated from normal human gut epithelium display phenotypical features different from their counterparts in peripheral blood. Europ. J. lmmunoi., 20, 1097.

H. Spits, H. Yssel and J.E. de Vries:

Selection o f V~9V82 using TCR'(8 + cells in the human foetal thymus.

It is intriguing that the V-f9V82 pair is expressed predominantly in early foe- tal development. As indicated by Trie- bel, it is very well possible that these cells are positively selected in the foetal thymus, although it cannot be formal- ly excluded that cells that rearrange V~9 to J's other than JP or that join V-fl0 or 11 are negatively selected. If the cells are positively selected, the "selecting" antigen is perhaps expressed in the thy- mus only in early foetal development and not af ter bir th, because V~,9V82-positive cells are rare in the postnatal thymus. As indicated by Bol- huis and colleagues, most if not all V'r9V82-expressing cells recognize an antigen on Daudi cells. We have found that foetal TCR3,8 + thymocyte clones expressing V'r9 and V82 respond to Daudi by producing cytokines, but do not lyse Daudi cells. It is suggested that Daudi cells express a 58-kDa stress pro-

tein, which may be the target antigen recognized by the V-f9V~2-positive cells. It ma) also be possible that Daudi .ells express the ligand molecule that selects the V~,9V~,2-expressing .. . . . C e l l S .

It should also be noted that foetal TCR~'8 + thymocyte clones produce sig- nificant levels of IL-4 and IL-5, while postnatal thymocyte clones fail to produce those cytokines (Krangel et aL, 1990, J. exp. Med. , 172, 847). IL-4 is known to have profound effects on T-cell growth and probably also on differentiation. It is possible that V-f9V82* foetal thymocytes produce IL-4 in vivo after activation with anti- gens expressed in certain parts of the foetal thymus and thereby influencing growth and /or differentiat ion of TCR0t[3 + T cells. However, we have yet to demonstrate that foetal V-r9V82 cells produce IL-4 or other cytokines in vivo. One should realize that using the termi- nology "positive selection" does not im- ply that TCR~,8+ are selected in the same way as TCR0~13 ÷ T cells, In a re- cent workshop about TCR'f8 + T cells held in Schloss Elmau, Germany, it was

Page 2: H. Spits, H. Ysell and J.E. de Vries

678 33 rd F O R U M I N I M M U N O L O G Y

reported that cyclosporin A, which blocks maturation of TCRa[3+ T cells, does not affect maturation of TCR~,~+ T cells in mouse foetal thymic organ cultures. This suggests that the mechan- isms of selection of TCRa[3 + and -f~ + are different.

A re TCR.(~ + T cells evolved to distin- guish "'stressed f r o m non-stressed" cells or to recognize bacterial products ?

Several contributions deal with the question as to whether TCR~.~ + T cells are specialized to recognize stress pro- teins. Although it has been established that some TCR7~÷ T cells can recog- nize 60-kDa hsp, it is by no means cer- tain that TCR'r~ ÷ T cells in general are specialized to recognize stress proteins. TCRa[3 + T cells have also been shown to recognize 60-kDa hsp both in man and mouse. Based on the finding that human TCR0~[3+ T ceils have been shown to recognize autologous stress proteins (Lamb et al., Intern. lm- munol. , 1, 191, 1989), one may argue that some TCR~[3+ T cells, which are the predominant CD3 ÷ T cells in hu- man skin, are specialized to recognize stress proteins and serve to protect the integrity of the skin epithelium. It is not !ikelv tha~ rhi~ i,~ t r n ~ Tho nrodilo~tlnn of---Tffk-~+-- ;1: ceils "iin"p'~arii'cu'la'r V~,9V~2 + T ceils in man) for mycobac- teria, as showa by Kaufmann et aL and Band et al., does not necessarily mean that those cells are specialized to recog- nize (myco)bacterial products. The response of human V~.9V~2 ÷ cells to the yet undefined (myco)bacterial anti- gens is typical for a "superantigen" response. Such a response can also be mediated by TCRa[3+ T ceils. We favour the notion put forward by Blue- stone that TCR0~[3 and -f~ receptors are fundamentally not that different, although the "r and B loci contain much less V gene segments than the ~ and [3 loci. however, TCR0t[3 process a sophisticated co-recognition system (CD4 and CD8) that allows a very effi- cient recognition of low doses of anti- genic peptide. The great majority of TCR-fB+ T cells lack this corecognition system. (One may argue that TCR-f8+

T cells can express CD8. However, CD8 is expressed as an cx-cx homodimer on TCR-f~+ T cells, which may be far less efficient to serve as a coreceptor than the CD8~[3 heterodimer found on TCR0t[3+ T cells.) Since CD4 and CD8 are involved in signalling, it seems like- ly that the absence of those coreceptor molecules has implications for the way the TCR~.~+ T cells transduce signals received by its receptor. Apart from CD4 and CD8, there may also be other differences between TCR~[3 and ~.8 T cells that affect signalling. For exam- ple, TCR~.~+ clones from thymus (Krangel et aL, J. exp. Med., 172, 847, 1990) and from PBL (H. Spits, unpub- lished) produce cytokines after stimula- tion with the phorbol ester PMA alone, while cytokine production by TCR~[3 + T-cell clones require both PMA and anti-CD3 mAb. As Bluestone remarked, our understanding of growth require- ments and signalling in these cells is poor. Therefore, it is our ooinion that, although further analysis of antigens that can" be recognized by TCRy~+ T ceils is necessary, much needs to be learned about how the TCR~.~+ T cells process and respond to the signals they receive via the TCR by making cytokines and mediating cytotoxicity. This would help to understand what role TCRv8 + T cells play in the immune response.

A.J. Gatri i i , M.E. Munk and S.H.E. Kaufmann:

The collective contributions to this Forum in Immunology highlight the fact that it is still unclear (1) what "r/~ T-cells " s e e " with their TCR, (2) whether and which restriction ele- ments are used, (3) whether signalling through the "r/~ TCR is a sole (or abso- lute) requirement for activation, or (4) which functions ~,/~ T cells may per- form once activated.

In this reply, we would like first to comment on those observations report- ed by others which are closedly related to our own studies on ~,/~ T cells react- ing to bacterial antigens. As described above, we have noted an expansion of