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Ir genes of the major histocompatibility complex
408
2e FOllUM D ' I M M U N O L O G I E
Ir GENES OF T H E MAJOR H I S T O C O M P A T I B I L I T Y COMPLEX by H . v o n B o e h m e r
Basel Institute/or Immunologg, Grenzacherstrasse 487, CH-4005, Basel (Swilzerland) We worked experimentally on MHC Ir genes from 1974 to 1979. In 1974, there were contrasting hypotheses. One by Benacerraf [2] which can be summarized by one sentence: (( We must come to the inescapable conclusion that there exists a class of molecules encoded by H-linked Ir genes which are responsible for the recognition of specificity at the T-cell level, and t h a t these molecules are not Ig ,. The other by Jerne [10]: (( H-antigens determine which of an animal's V-genes will be available for generation of antibody diversity by the selection of m u t a n t ceils ,. In Benacerraf's view, MHC Ir genes encode the T-cell receptor; in Jerne's view, they encode MHC antigens. In 1974, we had not only contrasting hypotheses but also incompatible experimental data: experiments by Bechthol et al. [1] were interpreted to support the view t h a t the MHC genotype of T cells correlated with their specificity: in allophenic mice constructed of a high and low responder strain to the antigen TGAL, B cells of the high as well as of the low responder strain produced TGAL-specific antibodies. These data were incompatible with data obtained by K a t z el al. [11] as well as by Shevach and Hosenthal [18]: T cells from an FI hybrid between a high and low responder strain only interacted with high responder but not low respontier B cells or macrophages. In 1974, we followed Jerne's suggestion [10]: ~(Allophenic mice from two inbred strains, one of which is a responder and the other a non-responder.., might be useful for disproving my hypothesis. The theory predicts t h a t the responding cells include cells of each of the partner strains ~. We did not make allophenic mice but haemopoietic chimeras with bone marrow from two ti-2 different strains. Since, according to the experiments by K a t z el al. [11] and Shevach and Rosenthal [18] MHC restriction was in some way associated with Ir-gene control, we first showed t h a t T cells from one partner strain could cooperate with B cells from the other partner strain [5]. When we reviewed these data [6], we read in the same volume, by Doherty el al. [8]: (( We need to determine whether it is possible to generate virus-immune cytotoxic T cells of one H-2 type against virus-infected cells of another H-2 type and successful immunization across an H-2 barrier would support the altered self hypothesis ~). I do not necessarily agree with their conclusion, but we had done the proposed experiment with T helper ceils and this, for the first time, ruled out the idea t h a t MHC-restricted T cells were genetically programmed to interact only with syngeneic cells. In fact, with T ceils from chimeras, we found no preference for syngeneie cells. We then proceded to test whether T cells from a low responder strain obtained from a chimera would phenotypically behave like T cells from a high responder strain. After failures to obtain significant T-cell responses to antigens GAT and TGAL, we studied the cytotoxic response to H Y as described by Gordon et al. (J. exp. Med., 1975, 142, 1108-1120). IIere, we finally showed t h a t T cells from a low responder strain raised in a responder environment behaved phenotypically like responder T cells [7]. This experiment was probably the first to rule out t h a t
Ir GENES
409
MttC Ir genes controlled immune responses because they encode antigen-specific receptors on T cells, and therefore disproved the original hypothesis by Benacerraf [2]. This was contrary to the belief of some authors that T-cell specificity was at least in part determined by MHC-linked genes [13, 12]. When the experiments wcrc published, we read [3]: (( Allowing non-responder type T-cell precursors to differentiate in rcsponder-type thymus should yield mature T cells of non-responder type able to be triggered by responder-type macrophages. Experiments along these lines may well prove extremely valuable for increasing our knowledge about T-cell antigen recognition, T-cell receptors and Ir-genc function ),. This reads like an updated (it includes MHC restriction) baroque version of Jerne's prediction. We found t h a t low rcsponder T cells were restricted by high responder MHC antigens only, an experiment incompatible with the original notion by Bechtol [1]. (A re-evaluation in McDevitt's laboratory had shown that, in fact, in the allophenic mice, no TGAL-speciiic antibody of low responder allotype could be found [15]). Our experiment, together with those reported by Katz et al. [11] and Shevach and Rosenthal [18] showed that - - as predicted by Jerne - - Ir-gene products were MHC antigens. (Some authors claim that blocking of responses by antibodies showed the identity of MHC and Ir genes. In my opinion, these studies only showed t h a t T cells are restricted by MHC antigens, which was known anyway from experiments with H-2 mutants). In the discussion of our paper 17], Jerne augmented his original theory to include MHC restriction. In fact, it is MHC restriction which makes explanations of MHC Ir genes, other than Jernc's, possible: before MtlC restriction was discovered, it was impossible to imagine that self-tolerance was responsible for nonresponsiveness, since high • responder F1 hybrid animals always responded. However, in those hybrids, restriction to low responder MHC antigens is not observed, and therefore one might argue t h a t non-responsiveness is the result of MHC-restricted tolerance [17]. Another explanation made possible by MHC restriction is that low responder MHC antigens cannot form immunogeneic complexes with certain antigens [16, 4[. It would appear that some experiments [9] suggest that the latter model does not explain all cases of non-responsiveness. These experiments, as pointed out in one of the more thoughtful discussions [14], do not, however, distinguish between the proposals of Schwartz and Jerne. In conclusion, I think that cellular immunologists could give some definitive answers (even with haemopoictic chimeras) to questions concerned with MHC Ir genes. Cellular immunologists were not clever enough to answer all questions before molecular biologists entered the field. Re[erences.
[1] B~CHTHOL, R. B., FREED, J. H., HERZENBEna, L. A. & McDEVITT, H. 0., Genetic control of the antibody response to TGAL in C3H-CWB tetraparcntal mice. J. exp. Med., 1974, 140, 1660. [2] BENACERRAF, B., The genetic mechanisms that control the immune response and antigen recognition. Ann. Immunol. (Inst. Pasleur), 1974, 125 C, 143-164. [3] BENAcEnnAF, B. & GERS[AIN, R., The immune response genes of the major histocompatibility complex. Transplant. Trey., 1978, 38, 70. [4] BENACERnAF, B., A hypothesis to relate the specificity of T lymphocytes and the activity of I region specific h" genes in macrophages and B lymphocytes. J. Immtmol., 1978, 120, 1809. [5] von BOEHMER, H., HUDSON',I,. & SPRENT, J., Collaboration of histoincompatible T and B lymphocytcs using ceils from tetraparental bone marrow chimeras. J. exp. Med., 1975, 142, 989. [6] yon BOEHMER, H. & SPRENT, J., T-cell function in bone marrow chimeras: absence of host-reactive T cells and cooperation of T helper cells across allogeneic barriers. Transplant. Bey., 1976, 29, 3. [7] von BOEHMEn, I-I., I-tAAS, W. & JEnNE, N. K., MHC-linked immune responsiveness is acquired by lymphocytes of low responder mice differentiating in
410
[8] [9] [10] [11]
[12]
[13] [14] [15]
[16] [17] [18]
2e FORUM D'IMMUNOLOGIE the thymus of high responder mice. Proc. nat. Acad. Sci. (Wash.), 1978, 75, 2439. DOHERTY, P. C., BLANDEN, R. V. & ZINKERNAGEL, R. M., Specificity of virusimmune effector T cells for H-2K or H-2D compatible interactions: implications for H-antigen diversity. Transplant. Rev., 1976, 29, 89-124. ISHII, N., BAXEVANIS, C. N., NAGY, Z. A. & KLEIINr,J., Responder T cells depleted of alloreactive cells react to antigen presented on allogeneic macrophages from non-responder strains. J. exp. Med., 1981, 154, 978. JEnNE, N. K., The somatic generation of immune recognition. Europ. J. lmmunol., 1971, 1, 1. KATZ, D. H., HAMAOKA, T., DORF, M. E., MAURER, P. H. & BENACERI1AF,B., Cell interactions between histocompatible T and B l y m p h o c y t e s . - IV. Involvement of the immune response (Ir) gene in the control of lymphocyte interactions in responses controlled by the gene. d. exp. Med., 1973, 138, 734. MosEs, E., The nature of antigen-specific T cell factors involved in the genetic regulation of immune responses, in (~ The role of products of the histocompatibility complex in immune responses ,). (D. H. Kak & B. Benacerraf) (p. 485), Academic Press, London, New York, 1976. MUNRO, A. J. & TAUSSlG, M. J., Two genes of the MHC control immune response. Nature (Lond.), 1975, 256, 103. NAGY, Z. A., ISHII, N., BAXEVANIS, C. N. & KLEIN, J., Lack of Ir gene control in T cell responses restricted by allogeneic MHC molecules. Behring Inst. Res. Commun., 1982, 70, 74. PRESS, J. L. & McDEvITT, H. O., Allotype specific analysis of anti TGAL antibodies produced b y Ir-IA high and low responder chimera mice. J. exp. Meal., 1977, 146, 1815. ROSENTHAL,A. S., Determinant selection and macrophage function in genetic control of the immune response. ImmunoI. Rev., 1978, 40, 136. SCHWARTZ, R. H., A clonal deletion model for Ir-gene control of the immune response. Scan& J. Immunol., 1978, 7, 3. SHEVACH, E. M. & I~OSENTHAL,A. S., The function of macrophages in antigen recognition of guinea-pig T lymphocytes. - - II. Role of the macrophage in the regulation of genetic control of the immune response. J. exp. Med., 1973, 138, 1213.
H-2 AND NON-H-2 Ir GENES by E. S i m p s o n Clinical Research Cenlre Harrow, Middlesex H A 1 3 U J ( U K )
One of the principal concerns of immunology is w h a t controls immune responSiveness: why do certain individuals respond, with antibody and/or activated T cells, to a particular antigen, whilst others do not? There are clearly genetic and environmental factors involved, and the term (~ Ir genes )~is usually t a k e n to mean the sum of genetic factors, although this m a y also involve interplay with environmental influences, which, during the lifetime of an individual or l y m p h o c y t e s isolated from an individual, shape the receptor repertoire by selection and perhaps somatic mutation. The genes most studied in their role as Ir genes are those of the m a j o r histocompatibility complex (MHC). Both class I and class I I MHC genes can serve this role, and this is manifest b y the function of their t r a n s m e m b r a n e glycoprotein products as restriction elements for the recognition of extrinsic antigen b y T cells.
2e FOllUM D ' I M M U N O L O G I E
Ir GENES OF T H E MAJOR H I S T O C O M P A T I B I L I T Y COMPLEX by H . v o n B o e h m e r
Basel Institute/or Immunologg, Grenzacherstrasse 487, CH-4005, Basel (Swilzerland) We worked experimentally on MHC Ir genes from 1974 to 1979. In 1974, there were contrasting hypotheses. One by Benacerraf [2] which can be summarized by one sentence: (( We must come to the inescapable conclusion that there exists a class of molecules encoded by H-linked Ir genes which are responsible for the recognition of specificity at the T-cell level, and t h a t these molecules are not Ig ,. The other by Jerne [10]: (( H-antigens determine which of an animal's V-genes will be available for generation of antibody diversity by the selection of m u t a n t ceils ,. In Benacerraf's view, MHC Ir genes encode the T-cell receptor; in Jerne's view, they encode MHC antigens. In 1974, we had not only contrasting hypotheses but also incompatible experimental data: experiments by Bechthol et al. [1] were interpreted to support the view t h a t the MHC genotype of T cells correlated with their specificity: in allophenic mice constructed of a high and low responder strain to the antigen TGAL, B cells of the high as well as of the low responder strain produced TGAL-specific antibodies. These data were incompatible with data obtained by K a t z el al. [11] as well as by Shevach and Hosenthal [18]: T cells from an FI hybrid between a high and low responder strain only interacted with high responder but not low respontier B cells or macrophages. In 1974, we followed Jerne's suggestion [10]: ~(Allophenic mice from two inbred strains, one of which is a responder and the other a non-responder.., might be useful for disproving my hypothesis. The theory predicts t h a t the responding cells include cells of each of the partner strains ~. We did not make allophenic mice but haemopoietic chimeras with bone marrow from two ti-2 different strains. Since, according to the experiments by K a t z el al. [11] and Shevach and Rosenthal [18] MHC restriction was in some way associated with Ir-gene control, we first showed t h a t T cells from one partner strain could cooperate with B cells from the other partner strain [5]. When we reviewed these data [6], we read in the same volume, by Doherty el al. [8]: (( We need to determine whether it is possible to generate virus-immune cytotoxic T cells of one H-2 type against virus-infected cells of another H-2 type and successful immunization across an H-2 barrier would support the altered self hypothesis ~). I do not necessarily agree with their conclusion, but we had done the proposed experiment with T helper ceils and this, for the first time, ruled out the idea t h a t MHC-restricted T cells were genetically programmed to interact only with syngeneic cells. In fact, with T ceils from chimeras, we found no preference for syngeneie cells. We then proceded to test whether T cells from a low responder strain obtained from a chimera would phenotypically behave like T cells from a high responder strain. After failures to obtain significant T-cell responses to antigens GAT and TGAL, we studied the cytotoxic response to H Y as described by Gordon et al. (J. exp. Med., 1975, 142, 1108-1120). IIere, we finally showed t h a t T cells from a low responder strain raised in a responder environment behaved phenotypically like responder T cells [7]. This experiment was probably the first to rule out t h a t
Ir GENES
409
MttC Ir genes controlled immune responses because they encode antigen-specific receptors on T cells, and therefore disproved the original hypothesis by Benacerraf [2]. This was contrary to the belief of some authors that T-cell specificity was at least in part determined by MHC-linked genes [13, 12]. When the experiments wcrc published, we read [3]: (( Allowing non-responder type T-cell precursors to differentiate in rcsponder-type thymus should yield mature T cells of non-responder type able to be triggered by responder-type macrophages. Experiments along these lines may well prove extremely valuable for increasing our knowledge about T-cell antigen recognition, T-cell receptors and Ir-genc function ),. This reads like an updated (it includes MHC restriction) baroque version of Jerne's prediction. We found t h a t low rcsponder T cells were restricted by high responder MHC antigens only, an experiment incompatible with the original notion by Bechtol [1]. (A re-evaluation in McDevitt's laboratory had shown that, in fact, in the allophenic mice, no TGAL-speciiic antibody of low responder allotype could be found [15]). Our experiment, together with those reported by Katz et al. [11] and Shevach and Rosenthal [18] showed that - - as predicted by Jerne - - Ir-gene products were MHC antigens. (Some authors claim that blocking of responses by antibodies showed the identity of MHC and Ir genes. In my opinion, these studies only showed t h a t T cells are restricted by MHC antigens, which was known anyway from experiments with H-2 mutants). In the discussion of our paper 17], Jerne augmented his original theory to include MHC restriction. In fact, it is MHC restriction which makes explanations of MHC Ir genes, other than Jernc's, possible: before MtlC restriction was discovered, it was impossible to imagine that self-tolerance was responsible for nonresponsiveness, since high • responder F1 hybrid animals always responded. However, in those hybrids, restriction to low responder MHC antigens is not observed, and therefore one might argue t h a t non-responsiveness is the result of MHC-restricted tolerance [17]. Another explanation made possible by MHC restriction is that low responder MHC antigens cannot form immunogeneic complexes with certain antigens [16, 4[. It would appear that some experiments [9] suggest that the latter model does not explain all cases of non-responsiveness. These experiments, as pointed out in one of the more thoughtful discussions [14], do not, however, distinguish between the proposals of Schwartz and Jerne. In conclusion, I think that cellular immunologists could give some definitive answers (even with haemopoictic chimeras) to questions concerned with MHC Ir genes. Cellular immunologists were not clever enough to answer all questions before molecular biologists entered the field. Re[erences.
[1] B~CHTHOL, R. B., FREED, J. H., HERZENBEna, L. A. & McDEVITT, H. 0., Genetic control of the antibody response to TGAL in C3H-CWB tetraparcntal mice. J. exp. Med., 1974, 140, 1660. [2] BENACERRAF, B., The genetic mechanisms that control the immune response and antigen recognition. Ann. Immunol. (Inst. Pasleur), 1974, 125 C, 143-164. [3] BENAcEnnAF, B. & GERS[AIN, R., The immune response genes of the major histocompatibility complex. Transplant. Trey., 1978, 38, 70. [4] BENACERnAF, B., A hypothesis to relate the specificity of T lymphocytes and the activity of I region specific h" genes in macrophages and B lymphocytes. J. Immtmol., 1978, 120, 1809. [5] von BOEHMER, H., HUDSON',I,. & SPRENT, J., Collaboration of histoincompatible T and B lymphocytcs using ceils from tetraparental bone marrow chimeras. J. exp. Med., 1975, 142, 989. [6] yon BOEHMER, H. & SPRENT, J., T-cell function in bone marrow chimeras: absence of host-reactive T cells and cooperation of T helper cells across allogeneic barriers. Transplant. Bey., 1976, 29, 3. [7] von BOEHMEn, I-I., I-tAAS, W. & JEnNE, N. K., MHC-linked immune responsiveness is acquired by lymphocytes of low responder mice differentiating in
410
[8] [9] [10] [11]
[12]
[13] [14] [15]
[16] [17] [18]
2e FORUM D'IMMUNOLOGIE the thymus of high responder mice. Proc. nat. Acad. Sci. (Wash.), 1978, 75, 2439. DOHERTY, P. C., BLANDEN, R. V. & ZINKERNAGEL, R. M., Specificity of virusimmune effector T cells for H-2K or H-2D compatible interactions: implications for H-antigen diversity. Transplant. Rev., 1976, 29, 89-124. ISHII, N., BAXEVANIS, C. N., NAGY, Z. A. & KLEIINr,J., Responder T cells depleted of alloreactive cells react to antigen presented on allogeneic macrophages from non-responder strains. J. exp. Med., 1981, 154, 978. JEnNE, N. K., The somatic generation of immune recognition. Europ. J. lmmunol., 1971, 1, 1. KATZ, D. H., HAMAOKA, T., DORF, M. E., MAURER, P. H. & BENACERI1AF,B., Cell interactions between histocompatible T and B l y m p h o c y t e s . - IV. Involvement of the immune response (Ir) gene in the control of lymphocyte interactions in responses controlled by the gene. d. exp. Med., 1973, 138, 734. MosEs, E., The nature of antigen-specific T cell factors involved in the genetic regulation of immune responses, in (~ The role of products of the histocompatibility complex in immune responses ,). (D. H. Kak & B. Benacerraf) (p. 485), Academic Press, London, New York, 1976. MUNRO, A. J. & TAUSSlG, M. J., Two genes of the MHC control immune response. Nature (Lond.), 1975, 256, 103. NAGY, Z. A., ISHII, N., BAXEVANIS, C. N. & KLEIN, J., Lack of Ir gene control in T cell responses restricted by allogeneic MHC molecules. Behring Inst. Res. Commun., 1982, 70, 74. PRESS, J. L. & McDEvITT, H. O., Allotype specific analysis of anti TGAL antibodies produced b y Ir-IA high and low responder chimera mice. J. exp. Meal., 1977, 146, 1815. ROSENTHAL,A. S., Determinant selection and macrophage function in genetic control of the immune response. ImmunoI. Rev., 1978, 40, 136. SCHWARTZ, R. H., A clonal deletion model for Ir-gene control of the immune response. Scan& J. Immunol., 1978, 7, 3. SHEVACH, E. M. & I~OSENTHAL,A. S., The function of macrophages in antigen recognition of guinea-pig T lymphocytes. - - II. Role of the macrophage in the regulation of genetic control of the immune response. J. exp. Med., 1973, 138, 1213.
H-2 AND NON-H-2 Ir GENES by E. S i m p s o n Clinical Research Cenlre Harrow, Middlesex H A 1 3 U J ( U K )
One of the principal concerns of immunology is w h a t controls immune responSiveness: why do certain individuals respond, with antibody and/or activated T cells, to a particular antigen, whilst others do not? There are clearly genetic and environmental factors involved, and the term (~ Ir genes )~is usually t a k e n to mean the sum of genetic factors, although this m a y also involve interplay with environmental influences, which, during the lifetime of an individual or l y m p h o c y t e s isolated from an individual, shape the receptor repertoire by selection and perhaps somatic mutation. The genes most studied in their role as Ir genes are those of the m a j o r histocompatibility complex (MHC). Both class I and class I I MHC genes can serve this role, and this is manifest b y the function of their t r a n s m e m b r a n e glycoprotein products as restriction elements for the recognition of extrinsic antigen b y T cells.