- Email: [email protected]
I-region genes and the T-cell repertoire
Ir GENES
65
[5] KATZ,M., MAIZELS, R., WICKER, L., MILLER,A. & SERCARZ, E. E., Europ. J. Immunol., 1982, 12, 535-540. [6] MANCA,F., CLARKE,J., SERCARZ,E. E. & MILLER,A., in 5th Ir Gene Symposium, (( Ir genes: past, present and future ))(C. Pierce, S. Cullen, B. Schwartz, J. Kapp & D. Shreffier). Humana Press, Clifton NJ, 1983. [7] SCHWARTZ,l~., HANSBURG,D. & HEBER-KATz,E., ibid.
[8] GOODMAN,J. =~V. & SERCARZ, E., Ann. Rev. Immunol., 1983, i, 465-468. [9] KATZ,M. E., MILLER,A., KRZYCH,U., WICKER, L., MAIZELS,R., CLARKE,J., SHASTRI, N., OKI, A. & SERCARZ, E., in 5th Ir gene Symposium, op. cir. [10] KRZYCH,U., FOWLER, A. & SERCARZ, E. E., in ,( Protein conformation as an immunologic signal (F. Celada, V. Schumaker & E. E. Sercarz). Plenum Press, London, 1983. [11] YOWELL, R. L., ARANEO, B. A., MILLER, A. & SERCARZ, E. E., N a t u r e (Lond.), 1979, 279, 70-71. [12] SADEGR-NASSERI, S., KIPP, D., TAYLOR, B., MILLER,A. & SERCARZ, E. E., in manuscript. This work was supported by N I H grants A I - 1 1 1 8 3 and CA-24412, and grant $801217 from the Muscular Dystrophy Association. N. S. is a postdoctoral fellow of the L e u k e m i a Society of America. We would like lo thank the m a n y colleagues in the laboratory whose work, ideas and discussions orovided a basis for this synthesis.
I-REGION GENES AND T H E T-CELL R E P E R T O I R E by M. S e m a n Laboraloire d' ImmunodilTerencialion, Inslitut-Jacques Monod, CNRS, Universild Paris VII, 2 Place Jussieu, 75251 Paris Cedex 05 It is now well established that genes of the I region of the major histocompatibility complex (MHC) control ability to respond to a large variety of T-dependent antigens and influence the specificity of the T-cell repertoire. Historically, these genes received the name of immune response (Ir) genes. However, this denomination, which is convenient, is inappropriate since it is now clear that such genes do not exist. A large body of information based on genetical and serological investigations has demonstrated that Ir-gene products are, in fact, Ia or class II histocompatibility molecules. Accordingly, recent studies on the organization of the I region at the DNA level indicate that there are no genes in this region other than those encoding Ia antigens [1]. I-region gene control or self-Ia influence on the T-cell repertoire would therefore be a better formulation of a phenomenon which is of central interest in biology. The T-lymphocyte repertoire consists of clones recognizing foreign antigens together with self-histocompatibility molecules. This discovery gave rise to a large controversy as to whether I-region genes control the development of the repertoire during ontogeny or its expression upon antigenic stimulation. The first possibility is suggested by experiments with radiation-induced bone marrow chimeras, showing t h a t a non-responder phenotype can be modified by educating T cells in a responder thymic environment [2]. Unresponsiveness could therefore be the consequence of specific (( holes )) in the T-cell repertoire. These experiments, together with the observation that class II molecules are principally present on antigen-presenting cells (APC) and B cells, also excludes (( Ir-genes )) being expressed in T cells. The second possibility, called the determinant selection hypothesis [3, 4],
66
2 e FORUM D'IMMUNOLOG1E
is based on experiments suggesting that APC from non-responder animals cannot present antigen to T cells. Class II molecules would serve as a ((receptor ))for antigen on the APC membrane and unresponsiveness would result from a defcient interaction between antigen and this Ia receptor. Alternatively, T-helper cell expression in mice of the non-responder haplotype could be inhibited by suppressor T cells. Unresponsiveness, in that case, would be due to dominant suppression [5, 6]. Our approach to these questions was to investigate the response to haptencarrier conjugates using carrier molecules to which the response is under I-region gene control. These models, in the past, have contributed to the demonstration that I-region genes are involved in the control of T helper cell activation. With the DNP hapten, it was shown that immunization with DNP conjugates elicits anti-hapten antibody responses only when DNP is coupled to a carrier molecule to which the animal is a responder [7]. Unexpectedly, we observed that immunization with p-azobenzenearsonate (ABA) conjugated to the GAT synthetic polymer (ABAGAT) can induce anti-ABA antibody responses in both GAT responder and nonresponder animals [8]. This response is induced by GAT-specific T helper cells in GAT-responders and ABA-specific helpers in non-responder animals. I n d e e d , ABA-GAT-primed lymph node T cells from GAT responder mice proliferate in vitro in the presence of GAT or ABA-GAT, but not in the presence of ABAtyrosine (ABA-Tyr) or ABA. Conversely, T cells from GAT non-responders proliferate in the presence of ABA-GAT, ABA-Tyr or ABA, but fail to respond to GAT. Similarly, using the GT polymer to which most of the conventional inbred mice are non-responders, we showed that ABA-GT can recruit ABA-specific helper cells capable of inducing antibody responses to both ABA and GT epitopes [9]. Contrary to what has been reported in non-responders immunized with GT or GAT conjugated to methylated serum albumin (MBSA) [10], activation of GAT~ or GT-specific T helper ceils does not accompany the I-region-gene-controlled phenotype conversion of the antibody response. Yet, the recruitment of ABAspecific helper cells demonstrates that APC from non-responder mice can present ABA-GAT and ABA-GT to T cells. Even if antigen is processed by macrophages, it seems very likely thot ABA is presented, at least, coupled to carrier fragments. Hence, it suggests that unresponsiveness to GAT or GT is not the consequence of a deficient presentation by non-responder APC. This interpretation is in agreement with the results mentioned above in GAT-MBSA primed mice [10] and with the demonstration by Rock and Benacerraf [11] that GT competitively inhibits GAT presentation by GAT-responder APC, even though mice do not respond to GT. A large number of investigations have established the presence of antigenspecific suppressor T cells in non-responder animals immunized with GAT and GT polymers. Yet, whether suppressor cells really account for the non-responder phenotype, or are simply stimulated when the level of help is limited, remains questionable. First, in many systems, unresponsiveness is not due to dominant suppression. Second, in the GT suppressive model, which has been well studied, some strains do not produce one of the suppressive factors, and others are not susceptible to them [12], but, at the same time, they are non-responders to GT. This implies that another mechanism accounts for unresponsiveness. In H-2 b mice, the inability of APC to present the GT polymer can again be evoked since, in these mice, which are not susceptible to GT suppressive factors, GT does not inhibit GAT presentation in vitro [11]. Finally, GAT unresponsiveness is recessive in responder • non-responder F1 hybrids. Yet, few or no F1 T-cell clones recognize GAT in association with the I-A molecule of the non-responder type [13, 14]. Similarly, elimination of suppressor cells from the non-responder parental population by anti-Lyt-2 treatment suggests that these mice have only a limited number of GAT-specific helper cells [15]. Moreover, the GAT-specific suppressive pathway is initiated by a suppressor-inducer cell (TS1) secreting a factor which is not MHC-restricted [12]. If such a cell exists in F1 mice, accounting for the absence of clones restricted to the non-responder Ia, F1 mice could not be responders. These
Ir GENES
67
arguments suggest t h a t suppression might only be a secondary phenomenon occurring in mice presenting a deficiency in their T helper cell repertoire. The above comments seem to mean t h a t we favour the model of specific holes in the repertoire as the mechanism responsible for unresponsiveness even to GAT and GT polymers. This hypothesis is supported by a series of nice experiments in different systems [16, 17]. However, putting aside personal convictions, it may not be correct to conceive that a unique mechanism accounts for all non-responder phenotypes. The three theories proposed are not mutually exclusive. Faced with the impossibility of reconciling an enormous amount of conflicting data, we are forced to consider t h a t all three models could simultaneously be true [18]. This means that we may still be ignorant of the various possible roles of the MHC in the regulation of the immune response. For instance, why are cytotoxic T lymphocytes restricted to class I molecules and helper cells to class II? Or why, in the same mouse strain, are some antigens recognized in association with I-A and others with I-E class II molecules [19]? We have recently analysed the influence of I-region genes on the fine specificity of the T-cell repertoire to ABA in different inbred mice [20]. A comparison between responses to ABA, ABA-Tyr and ABAhistidine revealed the existence of at least four types of ABA-T-cell clones in the mouse. Expression of these different clones was clearly influenced by two sets of complementary genes. One of them could be mapped in the I region of the H-2 complex. The second corresponded to a gene(s) linked to the Ig heavy chain gene complex. Some strains, with the same H-2 haplotype, had different repertoires depending on the background gene(s). The association between antigen and Ia molecules on APC could not explain this situation. Yet, H-2 d mice responded to ABA-Tyr, but none of them could respond to ABA-His or ABA. APC, in this haplotype, may not have been able to present these molecules. Thus, even using very simple antigens, it is not possible to discriminate as to whether I-region genes participate in the definition of the available T-cell repertoire or whether they select the expressed repertoire. Our ignorance, despite numerous experimental approaches, of the structure and the genetic origin of the antigen-specific T-cell receptor(s) is, in part, responsible for the confusion t h a t still exists concerning the mechanisms of I-region-genecontrolled unresponsiveness. In the near future, when this information is available, antigen-specific immune defects will remain an essential tool for our understanding of acquisition and expression of the T-cell repertoire. I-region-gene-controlled deficiencies are, to cell mechanisms in immune regulation, what auxotrophic mutants were, in the past, to the establishment of the metabolic pathways in Escherichia coli. Re/erences.
[t] STEINMETZ, M., MINARD, K., HORVATH, S., McNIcHOLAS, J., STRELINGER, J., WAKE, C., LONG, E., MACH, B. & HOOD, L., Nature (Lond.), 1982, 300, 35. [2] LONGO, D., MATIS, A. & SCHWARTZ, R. H., CRC Critical Rev. Immunol., 1981, 2, 83. [3] I~OSENTHAL,A. S., Immunol. Rev., 1978, 40, 136. [4] F{OSENWASSER,L. J., BARCINSKI, M. A., SCHWARTZ,l:{. H. & I:{OSENTHAL,A. S., d. Immunol., 1979, 123, 471. [5] KAPP, J. A., PIERCE, C. W., SCHLOSSMAN,S. & BENACERRAF,B., J. exp. Med., 1974, 140, 648. [6] DEBRIS, P., KAPP, J. A. & BENACERRAF, B., J. exp. Med., 1975, 142, 1436. [7] GREEN, I., PAUL, W. E. & BENACERRAF, B., J. exp. Med., 1966, 123, 859. [8] SEMAN, M., t~EGNIER, D., HERMIER, B., & DURERT, J. M., J. Immunol., 1982, 129, 2082. [9] FLORES DE CASTANEDA, M., F{EGNIER, D., HERMIER, B., DUBERT, J. M. & SEMAN, M., Europ. d. Immunol., 1984 (in press). [10] AEANEO, B. A. & KAPP, J. A., J. Immunol., 1980, 124, 1492. [11] ROCK, K. L. & BENACERRAF, B., J. exp. Med., 1983, 157, 1618.
68
2 e FORUM D'IMMUNOLOGIE
[12] [13] [14] [15] [16] [17]
ARANEO,B. A. & KAPP, J. A., Immunigenet., 1980, 14, 221. KIMOTO, M., I(RENZ, T. J. • FATHMAN,C. G., J. exp. Med., 1981, 154, 883. REGNIER, D. & SEMAN, M., J. Immunol., 1983, 130, 573. GOUGEON, M. L. & THEZE, J., J. Immunol., 1983, 130, 1521. ISHII, N., NAGY, Z. A. ~r KLEIN, J., J. exp. Mecl., 1983, 157, 998. MATIS, L. A., LONGO, D. L., HEDRICK, S. M., HANNUM, C., MARGOLIASH, E. & SCHWARTZ,R. H., J. Immunol., 1983, 130, 1527. [18] HEDRICK, S. M., MATIS, L. A., HECHT, T. T., SAMELSON,L. E., LONGO, D. L., HEBER-KATZ, E. & SCHWARTZ,R. H., Cell, 1982, 30, 141. [19] NAGY, Z. A., BAXEVANIS, C. N., ISHII, N. ~r KLEIN, J., Immunol. Rev., 1981, 60, 59. [20] SEMAN, M., TRANNOY,E., FLORES DE CASTANEDA, M. & REGNIER, D., d. tool. Cell. Immunol., 1984 (in press).
THE
INTERACTIONS B E T W E E N A N T I G E N - P R E S E N T I N G CELLS (APC) AND T LYMPHOCYTES by I. R. C o h e n Department o[ Cell Biologg, The Weizmann Institute o[ Science, PO Box 26, Rehovot, 76100 (Israel)
Ir genes in the major histocompatibility complex (MHC) are important because they influence the magnitude and specificity of the immune response to particular epitopes and probably affect susceptibility to many diseases. A convincing amount of experimental evidence implicates APC and T lymphocytes as the cellular vehicles of Ir-gene effects. Various hypotheses have been put forth to explain the putative Ir-gene defect responsible for low responsiveness, the molecular basis of MHC restriction in APC-T lymphocyte communications, the nature of antigen processed by APC, the specificity of the T-lymphocyte receptor for autigen-MHC molecule and the possible influence of Ir genes on the T lymphocyte repertoire. My colleagues and I recently set out to provide molecular answers to these uestions and I shall review the results, hard and soft, under three headings: PC processing and presentation, T-lymphocyte receptor for antigen and the Ir-gene program. A P C processing and presentation. Because of its unprecedented affinity for the vitamin biotin [1], we chose to use the molecule avidin as an antigen to investigate molecular events in processing and presentation. The published results may be summarized as follows: 1. - - Ir genes in the H-21 region influenced the magnitude of the response to avidin through the agency of T lymphocytes [2]. 2. - - There was no detectable difference between high responder (H-2I 0 and low responder (H-2D) mice in uptake, degradation or release of a super-immunogenic processed avidin (PA) molecule that was about 1,000-fold more potent than native avidin (NA) [3]. 3. - - PA bound biotin, indicating that at least part of its native conformation was preserved in processing. As degraded avidin (non-biotin-binding) did not stimulate primed lymphocytes, it is possible that T lymphocytes recognize conformational antigenic determinants [3].
65
[5] KATZ,M., MAIZELS, R., WICKER, L., MILLER,A. & SERCARZ, E. E., Europ. J. Immunol., 1982, 12, 535-540. [6] MANCA,F., CLARKE,J., SERCARZ,E. E. & MILLER,A., in 5th Ir Gene Symposium, (( Ir genes: past, present and future ))(C. Pierce, S. Cullen, B. Schwartz, J. Kapp & D. Shreffier). Humana Press, Clifton NJ, 1983. [7] SCHWARTZ,l~., HANSBURG,D. & HEBER-KATz,E., ibid.
[8] GOODMAN,J. =~V. & SERCARZ, E., Ann. Rev. Immunol., 1983, i, 465-468. [9] KATZ,M. E., MILLER,A., KRZYCH,U., WICKER, L., MAIZELS,R., CLARKE,J., SHASTRI, N., OKI, A. & SERCARZ, E., in 5th Ir gene Symposium, op. cir. [10] KRZYCH,U., FOWLER, A. & SERCARZ, E. E., in ,( Protein conformation as an immunologic signal (F. Celada, V. Schumaker & E. E. Sercarz). Plenum Press, London, 1983. [11] YOWELL, R. L., ARANEO, B. A., MILLER, A. & SERCARZ, E. E., N a t u r e (Lond.), 1979, 279, 70-71. [12] SADEGR-NASSERI, S., KIPP, D., TAYLOR, B., MILLER,A. & SERCARZ, E. E., in manuscript. This work was supported by N I H grants A I - 1 1 1 8 3 and CA-24412, and grant $801217 from the Muscular Dystrophy Association. N. S. is a postdoctoral fellow of the L e u k e m i a Society of America. We would like lo thank the m a n y colleagues in the laboratory whose work, ideas and discussions orovided a basis for this synthesis.
I-REGION GENES AND T H E T-CELL R E P E R T O I R E by M. S e m a n Laboraloire d' ImmunodilTerencialion, Inslitut-Jacques Monod, CNRS, Universild Paris VII, 2 Place Jussieu, 75251 Paris Cedex 05 It is now well established that genes of the I region of the major histocompatibility complex (MHC) control ability to respond to a large variety of T-dependent antigens and influence the specificity of the T-cell repertoire. Historically, these genes received the name of immune response (Ir) genes. However, this denomination, which is convenient, is inappropriate since it is now clear that such genes do not exist. A large body of information based on genetical and serological investigations has demonstrated that Ir-gene products are, in fact, Ia or class II histocompatibility molecules. Accordingly, recent studies on the organization of the I region at the DNA level indicate that there are no genes in this region other than those encoding Ia antigens [1]. I-region gene control or self-Ia influence on the T-cell repertoire would therefore be a better formulation of a phenomenon which is of central interest in biology. The T-lymphocyte repertoire consists of clones recognizing foreign antigens together with self-histocompatibility molecules. This discovery gave rise to a large controversy as to whether I-region genes control the development of the repertoire during ontogeny or its expression upon antigenic stimulation. The first possibility is suggested by experiments with radiation-induced bone marrow chimeras, showing t h a t a non-responder phenotype can be modified by educating T cells in a responder thymic environment [2]. Unresponsiveness could therefore be the consequence of specific (( holes )) in the T-cell repertoire. These experiments, together with the observation that class II molecules are principally present on antigen-presenting cells (APC) and B cells, also excludes (( Ir-genes )) being expressed in T cells. The second possibility, called the determinant selection hypothesis [3, 4],
66
2 e FORUM D'IMMUNOLOG1E
is based on experiments suggesting that APC from non-responder animals cannot present antigen to T cells. Class II molecules would serve as a ((receptor ))for antigen on the APC membrane and unresponsiveness would result from a defcient interaction between antigen and this Ia receptor. Alternatively, T-helper cell expression in mice of the non-responder haplotype could be inhibited by suppressor T cells. Unresponsiveness, in that case, would be due to dominant suppression [5, 6]. Our approach to these questions was to investigate the response to haptencarrier conjugates using carrier molecules to which the response is under I-region gene control. These models, in the past, have contributed to the demonstration that I-region genes are involved in the control of T helper cell activation. With the DNP hapten, it was shown that immunization with DNP conjugates elicits anti-hapten antibody responses only when DNP is coupled to a carrier molecule to which the animal is a responder [7]. Unexpectedly, we observed that immunization with p-azobenzenearsonate (ABA) conjugated to the GAT synthetic polymer (ABAGAT) can induce anti-ABA antibody responses in both GAT responder and nonresponder animals [8]. This response is induced by GAT-specific T helper cells in GAT-responders and ABA-specific helpers in non-responder animals. I n d e e d , ABA-GAT-primed lymph node T cells from GAT responder mice proliferate in vitro in the presence of GAT or ABA-GAT, but not in the presence of ABAtyrosine (ABA-Tyr) or ABA. Conversely, T cells from GAT non-responders proliferate in the presence of ABA-GAT, ABA-Tyr or ABA, but fail to respond to GAT. Similarly, using the GT polymer to which most of the conventional inbred mice are non-responders, we showed that ABA-GT can recruit ABA-specific helper cells capable of inducing antibody responses to both ABA and GT epitopes [9]. Contrary to what has been reported in non-responders immunized with GT or GAT conjugated to methylated serum albumin (MBSA) [10], activation of GAT~ or GT-specific T helper ceils does not accompany the I-region-gene-controlled phenotype conversion of the antibody response. Yet, the recruitment of ABAspecific helper cells demonstrates that APC from non-responder mice can present ABA-GAT and ABA-GT to T cells. Even if antigen is processed by macrophages, it seems very likely thot ABA is presented, at least, coupled to carrier fragments. Hence, it suggests that unresponsiveness to GAT or GT is not the consequence of a deficient presentation by non-responder APC. This interpretation is in agreement with the results mentioned above in GAT-MBSA primed mice [10] and with the demonstration by Rock and Benacerraf [11] that GT competitively inhibits GAT presentation by GAT-responder APC, even though mice do not respond to GT. A large number of investigations have established the presence of antigenspecific suppressor T cells in non-responder animals immunized with GAT and GT polymers. Yet, whether suppressor cells really account for the non-responder phenotype, or are simply stimulated when the level of help is limited, remains questionable. First, in many systems, unresponsiveness is not due to dominant suppression. Second, in the GT suppressive model, which has been well studied, some strains do not produce one of the suppressive factors, and others are not susceptible to them [12], but, at the same time, they are non-responders to GT. This implies that another mechanism accounts for unresponsiveness. In H-2 b mice, the inability of APC to present the GT polymer can again be evoked since, in these mice, which are not susceptible to GT suppressive factors, GT does not inhibit GAT presentation in vitro [11]. Finally, GAT unresponsiveness is recessive in responder • non-responder F1 hybrids. Yet, few or no F1 T-cell clones recognize GAT in association with the I-A molecule of the non-responder type [13, 14]. Similarly, elimination of suppressor cells from the non-responder parental population by anti-Lyt-2 treatment suggests that these mice have only a limited number of GAT-specific helper cells [15]. Moreover, the GAT-specific suppressive pathway is initiated by a suppressor-inducer cell (TS1) secreting a factor which is not MHC-restricted [12]. If such a cell exists in F1 mice, accounting for the absence of clones restricted to the non-responder Ia, F1 mice could not be responders. These
Ir GENES
67
arguments suggest t h a t suppression might only be a secondary phenomenon occurring in mice presenting a deficiency in their T helper cell repertoire. The above comments seem to mean t h a t we favour the model of specific holes in the repertoire as the mechanism responsible for unresponsiveness even to GAT and GT polymers. This hypothesis is supported by a series of nice experiments in different systems [16, 17]. However, putting aside personal convictions, it may not be correct to conceive that a unique mechanism accounts for all non-responder phenotypes. The three theories proposed are not mutually exclusive. Faced with the impossibility of reconciling an enormous amount of conflicting data, we are forced to consider t h a t all three models could simultaneously be true [18]. This means that we may still be ignorant of the various possible roles of the MHC in the regulation of the immune response. For instance, why are cytotoxic T lymphocytes restricted to class I molecules and helper cells to class II? Or why, in the same mouse strain, are some antigens recognized in association with I-A and others with I-E class II molecules [19]? We have recently analysed the influence of I-region genes on the fine specificity of the T-cell repertoire to ABA in different inbred mice [20]. A comparison between responses to ABA, ABA-Tyr and ABAhistidine revealed the existence of at least four types of ABA-T-cell clones in the mouse. Expression of these different clones was clearly influenced by two sets of complementary genes. One of them could be mapped in the I region of the H-2 complex. The second corresponded to a gene(s) linked to the Ig heavy chain gene complex. Some strains, with the same H-2 haplotype, had different repertoires depending on the background gene(s). The association between antigen and Ia molecules on APC could not explain this situation. Yet, H-2 d mice responded to ABA-Tyr, but none of them could respond to ABA-His or ABA. APC, in this haplotype, may not have been able to present these molecules. Thus, even using very simple antigens, it is not possible to discriminate as to whether I-region genes participate in the definition of the available T-cell repertoire or whether they select the expressed repertoire. Our ignorance, despite numerous experimental approaches, of the structure and the genetic origin of the antigen-specific T-cell receptor(s) is, in part, responsible for the confusion t h a t still exists concerning the mechanisms of I-region-genecontrolled unresponsiveness. In the near future, when this information is available, antigen-specific immune defects will remain an essential tool for our understanding of acquisition and expression of the T-cell repertoire. I-region-gene-controlled deficiencies are, to cell mechanisms in immune regulation, what auxotrophic mutants were, in the past, to the establishment of the metabolic pathways in Escherichia coli. Re/erences.
[t] STEINMETZ, M., MINARD, K., HORVATH, S., McNIcHOLAS, J., STRELINGER, J., WAKE, C., LONG, E., MACH, B. & HOOD, L., Nature (Lond.), 1982, 300, 35. [2] LONGO, D., MATIS, A. & SCHWARTZ, R. H., CRC Critical Rev. Immunol., 1981, 2, 83. [3] I~OSENTHAL,A. S., Immunol. Rev., 1978, 40, 136. [4] F{OSENWASSER,L. J., BARCINSKI, M. A., SCHWARTZ,l:{. H. & I:{OSENTHAL,A. S., d. Immunol., 1979, 123, 471. [5] KAPP, J. A., PIERCE, C. W., SCHLOSSMAN,S. & BENACERRAF,B., J. exp. Med., 1974, 140, 648. [6] DEBRIS, P., KAPP, J. A. & BENACERRAF, B., J. exp. Med., 1975, 142, 1436. [7] GREEN, I., PAUL, W. E. & BENACERRAF, B., J. exp. Med., 1966, 123, 859. [8] SEMAN, M., t~EGNIER, D., HERMIER, B., & DURERT, J. M., J. Immunol., 1982, 129, 2082. [9] FLORES DE CASTANEDA, M., F{EGNIER, D., HERMIER, B., DUBERT, J. M. & SEMAN, M., Europ. d. Immunol., 1984 (in press). [10] AEANEO, B. A. & KAPP, J. A., J. Immunol., 1980, 124, 1492. [11] ROCK, K. L. & BENACERRAF, B., J. exp. Med., 1983, 157, 1618.
68
2 e FORUM D'IMMUNOLOGIE
[12] [13] [14] [15] [16] [17]
ARANEO,B. A. & KAPP, J. A., Immunigenet., 1980, 14, 221. KIMOTO, M., I(RENZ, T. J. • FATHMAN,C. G., J. exp. Med., 1981, 154, 883. REGNIER, D. & SEMAN, M., J. Immunol., 1983, 130, 573. GOUGEON, M. L. & THEZE, J., J. Immunol., 1983, 130, 1521. ISHII, N., NAGY, Z. A. ~r KLEIN, J., J. exp. Mecl., 1983, 157, 998. MATIS, L. A., LONGO, D. L., HEDRICK, S. M., HANNUM, C., MARGOLIASH, E. & SCHWARTZ,R. H., J. Immunol., 1983, 130, 1527. [18] HEDRICK, S. M., MATIS, L. A., HECHT, T. T., SAMELSON,L. E., LONGO, D. L., HEBER-KATZ, E. & SCHWARTZ,R. H., Cell, 1982, 30, 141. [19] NAGY, Z. A., BAXEVANIS, C. N., ISHII, N. ~r KLEIN, J., Immunol. Rev., 1981, 60, 59. [20] SEMAN, M., TRANNOY,E., FLORES DE CASTANEDA, M. & REGNIER, D., d. tool. Cell. Immunol., 1984 (in press).
THE
INTERACTIONS B E T W E E N A N T I G E N - P R E S E N T I N G CELLS (APC) AND T LYMPHOCYTES by I. R. C o h e n Department o[ Cell Biologg, The Weizmann Institute o[ Science, PO Box 26, Rehovot, 76100 (Israel)
Ir genes in the major histocompatibility complex (MHC) are important because they influence the magnitude and specificity of the immune response to particular epitopes and probably affect susceptibility to many diseases. A convincing amount of experimental evidence implicates APC and T lymphocytes as the cellular vehicles of Ir-gene effects. Various hypotheses have been put forth to explain the putative Ir-gene defect responsible for low responsiveness, the molecular basis of MHC restriction in APC-T lymphocyte communications, the nature of antigen processed by APC, the specificity of the T-lymphocyte receptor for autigen-MHC molecule and the possible influence of Ir genes on the T lymphocyte repertoire. My colleagues and I recently set out to provide molecular answers to these uestions and I shall review the results, hard and soft, under three headings: PC processing and presentation, T-lymphocyte receptor for antigen and the Ir-gene program. A P C processing and presentation. Because of its unprecedented affinity for the vitamin biotin [1], we chose to use the molecule avidin as an antigen to investigate molecular events in processing and presentation. The published results may be summarized as follows: 1. - - Ir genes in the H-21 region influenced the magnitude of the response to avidin through the agency of T lymphocytes [2]. 2. - - There was no detectable difference between high responder (H-2I 0 and low responder (H-2D) mice in uptake, degradation or release of a super-immunogenic processed avidin (PA) molecule that was about 1,000-fold more potent than native avidin (NA) [3]. 3. - - PA bound biotin, indicating that at least part of its native conformation was preserved in processing. As degraded avidin (non-biotin-binding) did not stimulate primed lymphocytes, it is possible that T lymphocytes recognize conformational antigenic determinants [3].