235

Immunology Today, vol. ,3, No. 9, 1982

(,°=,°..

I

Lyt antigens as markers for functional T-cell subpopulations The description of the Lyt series of diflerentiation antigens by Boyse and colleagues I has profoundly aided the identification of functionally distinct T-cell subpopulations and the demonstration of the complex interactions which can occur among these populations in the generation and regulation of immune responses. The first descriptions of the functional correlates of Lyt antigen expression contained a comforting consistency between the functional properties of a given T-cell population and its Lyt phenotype: Lyt 1+23 cells acted as T helper (T.) cells for both B-cell responses and T-cell responses, while Lyt 1 23 + cells were either T suppressor (Ts) cells or cytotoxic T cells 2-5. Since then, questions have been raised about the constancy of Lyt antigen expression by T cells. It was variously reported, for example, that Ts cells could be Lyt 1 23 + (Ref. 4-6), Lyt 1+23 (Refs. 7, 8), or Lyt I+23 + (Ref. 6) in phenotype, raising substantial doubts about the premise that a single Lyt phenotype is consistently associated with a given functional Tcell population. These conflicting results have not been resolved but the further use of Lyt phenotyping has demonstrated that T s cells are in fact not functionally homogeneous. Rather, there exist T s cell subpopulations which are functionally distinct from one another, and which interact with one another in highly ordered and complex regulatory circuits 9 1i. Moreover, it appears that each of these T s subpopulations expresses a different consistent Lyt phenotype. Thus, apparent inconsistencies in the relationship between Lyt phenotype and function have been shown to reflect at least in part a previously unappreciated complexity of T-cell functions. An additional perspective upon this issue has been provided by Swain and colleagues, who propose that Lyt phenotype may correlate more directly with the antigen specificity of T cells than with their class of effector function ~2. The suggestion has now been added to the literature that T . cells may express different Lyt phenotypes, depending upon the point at which they are analyzed during an antibody response 13. The reciprocal nature of this reported change, from Lyt 1+2- early in a secondary response to Lyt 1-2 + after boosting, makes it unlikely that this represents an artifact of altered general sensitivity of cells to the reagents employed and suggests that the cells mediating these two helper activities do in fact express different Lyt phenotypes. Perhaps this observation will increase our understanding of T Hcell function, e.g. by revealing a network of circuit interactions between the T-cell subpopulations involved in helper

functions, paralleling those observed for Ts cells. It will also be interesting to see if the cloning of T . cells provides evidence of an LytI-2 + subset, as this study would predict. So far all the cloned T cells that have been characterized are Lyt 1+2 - (Refs. 14, 15). A question has also been raised in recent years about the constancy of expression of Lyt phenotype over time by a given cell or cell lineage. A number of investigators have concluded that differentiated T cells of diverse Lyt phenotypes probably derive from a single Lyt 1+23 + precursor population I6,17, implying that Lyt phenotypes change during the differentiation process. Other data support the alternative conclusion that there are at least two distinct precursor lineages, one Lyt 1+23+ and the other 1+23 - (Ref. 18). However, the early studies were in agreement in the conclusion that functionally differentiated Lyt 1+23 and Lyt 1-23 + populations retain both their Lyt phenotypes and their functional capacities over time, even during prolonged 'parking' in irradiated Tdeprived hosts j6. Some more recent reports, however, have concluded that immunologically competent Lyt 1+23 + populations can be activated in vitro with concomitant changes in Lyt phenotype. It has been reported, for example, that Lyt 1+23 + cytotoxic T-cell precursors differentiate into Lyt 1 23 + effectors during activation in vitrolg; other studies have disagreed with this finding 20,2~. It has also been reported that Lyt 1 +23 + precursors can differentiate in vitro into either Lyt 1+23 - suppressor inducer cells or into Lyt 1+23 helper cells 22. Thomas and Calderon have now reported that the Lyt 1+2- T H cells present early in a secondary antibody response can differentiate in response to an antigen boost during parking ir~ vivo to generate an Lyt 1-2+Tn-cell population t3. They conclude that this transition in Lyt phenotype represents an altered expression of Lyt antigens by a single T Hcell population, and not the selective expansion of a separate and pre-existent Lyt 1-2 + cell lineage in vivo. They therefore suggest that the Lyt pbenotype expressed by functionally differentiated T cells is not immutable, but is altered in the course of functional activation. The explanation for the difference between these results and those of the original parking experiments of Huber and colleagues 16 is not clear, but presumably lies in the use of an 'appropriate' boosting regirnen to trigger the observed T-cell differentiation. It should be emphasized that these studies are based upon the behavior of enriched but potentially heterogeneous cell populations so that the distinction between altered Lyt expression by a single T-cell lineage and the selecElsevier Biomedical Press 1982 0167 4919/82/0000 0000/$1 0O

236

Immunology Today, vol. 3, No. 9, 1982

tive e x p a n s i o n of a pre-existent a n d unaltered subp o p u l a t i o n m a y be a difficult one. A more rigorous d e m o n s t r a t i o n would require the characterization of truly h o m o g e n e o u s (monoclonal) T-cell populations w h i c h exhibit c h a n g e s in Lyt p h e n o t y p e expression, for e x a m p l e in response to activation by antigen. T h e suggestion that T cells can alter their expression of Lyt antigens in response to a p p r o p r i a t e differentiative stimuli is not unreasonable. Well docUm e n t e d e x a m p l e s already exist for the altered expression of o t h e r differentiation markers, such as la antigens, by b o t h heterogeneous a n d m o n o c l o n a l populations in response to a p p r o p r i a t e signals 23-25. In addition, the possibility that the Lyt 2 antigen at least plays a direct role in certain T-cell functions suggests that the i n d u c e d differentiation of T-cell functions m a y well be paralleled by an alteration in expressed Lyt p h e n o t y p e 26-28. This p r e d i c t i o n will u n d o u b t e d l y be tested by further studies of differentiation in enriched a n d in m o n o c l o n a l T-cell populations. RICHARD J. ItODES Immunology Branch, National Cancer Institute, National Institutes qf Health, Bethesda, M D 20205, U.S.A.

References I Boyse, E. A., Miyazawa, M., Aoki, T. and Old, L.J. (1968) Proc. Roy. Soc. Lond. Ser. B. 170, 175-193 2 Cantor, H. and Boyse, E. A. (1975) J. Exp. Med. 141, 1376-1389 3 Cantor, H. and Boyse, E. A. (1975) J. Exp. Med. 141, 1390-1399 4 Jandinski, J., Cantor, H., Tadakuma, T., Peavy, D. L. and Pierce, C. W. (1976),7. Exp. Med. 143, 1382-1390 5 Cantor, H., Shen, F. W. and Boyse, E. A. (1976),7. Exp. Med. 143, 1391-1401 6 AI-Adra, W. R., Pilarski, L. M. and McKenzie, I. F. C. (1980) lmmuru;genet. 10, 52I-.533

7 Maier, T., Levy, J. G. and Kilburn, D. G. (1980) Cell. Immunol. 56, 392-399 8 Ramshaw, I. A., McKenzie, I. F. C., Bretscher, P. A. and Parish, C. R. (1977) Cell. ImmunoL 31,364-369 9 Eardley, D. D., Hugenberger, J., McVay-Boudreau, L., Shen, F. W., Gershon, R. K. and Cantor, It. (1978)J. Exp. Med. 147, 1106-1115 I0 McDougal, J. S., Shen, F. W., Cort, S. P. and Bard, J. (1980) J. lmmunol. 125, 1157-1 160 11 Germain, R. N. and Benacerraf, B. (1981) &and. J. hnmunol. 13, 1-10 12 Swain, S. L., Dennert, G., Wormsley, S. and Dutton, R. (1981) Eur. J. lmmunoL 11, 175-180 13 Thomas, D. B. and Calderon, R. A. (1982) Eur. J. Immunol. 12, 16-23

14 Schreier, M. H., Iscove, N. N., Tees, R., Aarden, L. and yon Boehmer, H. (1980) lmmunoL Rev. 51,315-336 15 .Jones, B. and Janeway, C. A. (1981) Nature (London) 292, 547-549 16 ltuber, B., Cantor, H., Shen, F. W. and Boyse, E. A. (1976) J. Exp. Med. 144, 1128-1133 17 Stutman, O. and Shen, F.-W. (1979) Transp. Proc. 11,907-909 18 Mathieson, B. J., Sharrow, S. O., Rosenberg, Y. and Hammerling, U. (1981) Nalure (London) 298, 179-181 19 Hardt, C., Pfizenmaier, K., Rollinghoff, M., Klein, J. and Wagner, H. (1980).7. Exp. Med. 152, 1413-1418 20 Teh, H.-S. and Teh, S.-J. (1980)J. humunoL 125, 1977-1986 21 Cerottini, J.-C. and MacDonald, H. R. (1981).7. Immunol. 126, 490496 22 Shen, F. W., McDougal, J. S., Bard, J. and Cort, S. P. (1980) J. Exp. Med. 151,566-572 23 Scher, M. G., Beller, D. I. and Unanue, E. R. (1980).7" Exp. Med. 152, 1684-1698 24 Walker, E. B., Lanier, L. L. and Warner, N. L. (1982) J. Exp. Med. 155,629-634 25 Birmingham, J. R., Chesnut, R. W, Kappler, J. W., Marrack, P., Kubo, R. and Grey, H. M. (1982) J. hnmunol. 128, 1491-1492 26 Nakayama, E., Shiku, H., Stockert, E., Oettgen, H. F. and Old, L.J. (1979) Proc.NatlAcad. Sci. U.S.A. 76, 1977-1981 27 Shinohara, N. and Sachs, D. H. (1979) J. Exp. Med. 150, 432~i44 28 Nakayama, E., Dippold, W., Shiku, H., Oettgen, H. F. and Old, L.J. (1980) Proc.Natl Acad. Sci. U.S.A. 77, 2890-2894

Further intricacy of HLA-DR antigens T h e substantial evidence that t h r e e loci encode h u m a n p o l y m o r p h i c class lI M H C antigens was revi6wed last m o n t h in Immunology Today ~. T o reiterate briefly, analysis of D R alloantisera displaying additional serological reactions led to the s i m u l t a n e o u s finding in several centres, of second locus multi-allelic systems of antigens in strong linkage disequilibrium with H L A - D R . T h e r e is still confusion about w h e t h e r or not antigens of the MB, M T , LB a n d D C series are, first, identical and, second, the p r o d u c t s of a single locus a l t h o u g h biochemical evidence suggests that the MB1, M T 1 , L B I 2 a n d DC1 specificities describe the same molecule 2. T h e M B locus antigens have molecular weights a n d isoelectricfocusing characteristics similar to those of D R antigens. T h e c o m b i n a t i o n of D R heavy chain a n d M B light chain has been s h o w n to comprise a t h i r d class II antigen species 2. A further multi-allelic s e c o n d a r y B-cell locus system (SB) m a p p i n g centromerically to I ) R has been described by S t e p h e n S h a w a n d his colleagues ~. SB © Elsevier Biomedical Press 1982 0167-4919/S2/0(}00-0000/$1.0II

antigens induce weak p r i m a r y allogeneic proliferative responses but secondary SB responses are as strong or stronger t h a n allogeneic D R responses. P r i m e d l y m p h o c y t e typing has so far been the only m e a n s of detecting SB antigens a n d the SB gene p r o d u c t s have not b e e n defined structurally. However, work on SB is now set to enter a serological phase: m o n o c l o n a l antibodies to class II n o n - p o l y m o r p h i c ' f r a m e w o r k ' determ i n a n t s inhibit SB-specific killing a n d a m o n o c l o n a l a n t i b o d y 4, ( I - L R 1 ) , has been m a d e w h i c h recognizes a supratypic d e t e r m i n a n t of SB antigens (Shaw, personal c o m m u n i c a t i o n ) . If as is likely, SB antigens share at least some features of D R antigens this puts the m i n i m u m n u m b e r of class I! 13 chain genes at three. Recently, however, K r a t z i n a n d colleagues have r e p o r t e d data w h i c h c o n s i d e r a b l y a d v a n c e unders t a n d i n g of the structure of h u m a n class II antigens a n d of the n u m b e r of 13 c h a i n genes e n c o d i n g t h e m 5. T h e entire a m i n o acid sequence of the 198 extra-

Lyt antigens as markers for functional T-cell subpopulations.

Lyt antigens as markers for functional T-cell subpopulations. - PDF Download Free
200KB Sizes 0 Downloads 5 Views