Two genes in the major histocompatibility complex control immune response

Munro, Alan; Taussig, Michael J.

doi:10.1038/256103a0

Cited by 276 publications

(94 citation statements)

References 20 publications

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“…Ia antigens are not expressed on PHA-stimulated lymphocytes (21) nor on P815 mastocytoma cells (22) and these populations do not adsorb suppressor molecules. Since Ia specificities are identified on normal (23) and mitogen-stimulated (9, 10, 21) B cells, it would be necessary to suggest a T-cell-restricted Ia expression, such as has been demonstrated for certain stimulator T cells in MLR (24)./-region gene control of other acceptor structures critical to regulatory T-cell interactions has been demonstrated (3,25). Although MLR responders have been described as functionally Ia negative by the criterion of anti-Ia serum-mediated cytotoxicity (26), it is possible that Ia is present but not defined under these conditions.…”

Section: Discussionmentioning

confidence: 99%

Regulatory mechanisms in cell-mediated immune responses. IV. Expression of a receptor for mixed lymphocyte reaction suppressor factor on activated T lymphocytes.

Rich¹,

Rich²

1976

The Journal of Experimental Medicine

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Proliferative responses in mixed lymphocyte reactions (MLR) 1 are suppressed by a soluble factor released by alloantigen-activated splenic T cells (1, 2). We have established that such suppressive T-cell factors derived from one strain only suppress responses of strains histocompatible for regions of the H-2 complex between I-E and D (1, 2). H-2-dissimilar MLR responder cells are unaffected by active suppressor factors. The data suggest that a receptor specific for that factor and required for an active suppressive interaction is expressed by genetically homologous cells. H-2-dissimilar responder cells would lack the appropriate genetically determined receptor and upon exposure to suppressor factors would be unaffected. A similar "acceptor" site for primed helper T-cell factor has been postulated on B cells (3). Genes mapped in the I region control functional expression of the acceptor, as well as interacting factor molecules. Thus it may be through association of such molecules, either released or on cell membranes, with B-cell surface structures that appropriate cell interactions in antibody synthesis are achieved.Accordingly we have tested the ability of cells, used as MLR responder cells, to adsorb suppressor factor activity as an indication of a receptor for MLR suppressor molecules. The results suggest that such a receptor structure is dynamically expressed by a subpopulation of T lymphocytes only after a triggering antigenic or mitogenic signal. The receptor is not present or perhaps not functional on resting cells. H.2 control of the receptor molecule is suggested by the inability of activated H-2-dissimilar T cells to interact with and remove suppressor activity. Materials and MethodsMice. BALB/c and DBA/2 mice were obtained from the

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Section: Discussionmentioning

confidence: 99%

Regulatory mechanisms in cell-mediated immune responses. IV. Expression of a receptor for mixed lymphocyte reaction suppressor factor on activated T lymphocytes.

Rich¹,

Rich²

1976

The Journal of Experimental Medicine

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“…They are not concerned with the general capacity to develop suppression, since DBA/1 (H-211) mice which develop suppressor T cells after GAT immunization are not specifically suppressed by GT and, therefore, lack the GT Is gene . Genetic similarities between H-linked Is and Ir genes are illustrated by the following observations : (a) Ir genes have been shown to be concerned with the expression of helper function in T-cell-dependent responses (6, 7) ; (b) helper and suppressor activity of T cells appear to be two related aspects of the regulatory activity ofthese cells on specific immune responses ; (c) the ability to mount antibody responses in systems under Ir gene control has been shown to be associated with the production of antigen-specific factors produced by responder T cells and endowed with helper activity for B cells (8,9) ; (d) similar antigen-specific factors with specific suppressor activity have been obtained from suppressor T cells (10)(11)(12); and (e) both helper and suppressor factors have similar molecular size and possess antigenic determinants coded for in the I region of the H2 complex (10,11,13).…”

Section: Discussionmentioning

confidence: 99%

“…The GTIs gene or genes should be precisely mapped within theH-2 complex ofthe mouse. Furthermore, we must determine whether two cooperative Is genes are needed to develop specific suppression as was shown to be the case in two systems for antibody responses under H-2-linked Ir gene control (9,15) . We must also determine at which cell levels the Is genes operate .…”

Section: Discussionmentioning

confidence: 99%

Genetic control of specific immune suppression. II. H-2-linked dominant genetic control of immune suppression by the random copolymer L-glutamic acid50-L-tyrosine50 (GT).

Debré¹,

Kapp²,

Dorf³

et al. 1975

The Journal of Experimental Medicine

102

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Several inbred as well as congenic resistant strains of mice, which fail to respond to the random copolymer of L-glutamic acid50-L-tyrosine50 (GT), were shown to develop specific PFC responses when stimulated by GT complexed to an immunogenic carrier such as methylated bovine serum albumin (MBSA). In these studies we have found that GT preimmunization has a tolerogenic effect on the response to GT-MBSA in some mouse strains; whereas in other strains of mice, GT fails to inhibit the GT-MBSA response. We may, therefore, conclude that immune suppression cannot account for nonresponsiveness in all cases. The development of specific immune suppression in response to GT was shown to be inherited as a dominant trait in F1 hybrids resulting from the mating of suppressor with nonsuppressor strains. This trait is, therefore, under the control of a gene or genes that we have designated as specific immune suppression gene(s) Is genes. The strain distribution of GT induced suppression demonstrates that Is genes are coded for in the H-2 complex. Furthermore, immune suppression by the two related copolymers, GT and GAT, are distinct in different strains of mice. The significance of these data for our understanding of the regulation of the immune response is discussed.

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“…After adsorption the sera were separated from the cells by centrifugation at 2000 rpm. The sera were then centrifuged in a Beckman Airfuge at 100,000 X g for [10][11][12][13][14][15] (Tables 2 and 3). It was our purpose in these experiments to test separately the inhibition of the GL4 response by antisera with specificity for the Ia antigens of the subregion coding for the (3 gene (I-A) and by antisera with specificity for the Ia antigens of the subregion coding for the a gene (I-E or I-C).…”

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confidence: 99%

Inhibition of dual Ir gene-controlled T-lymphocyte proliferative response to poly (Glu56Lys35Phe9)n with anti-Ia antisera directed against products of either I-A or I-C subregion.

Schwartz

David²,

Dorf

et al. 1978

Proc. Natl. Acad. Sci. U.S.A.

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Previous studies have demonstrated that both the antibody and T-lymphocyte proliferative immune responses to poly(Glu3Lys36Phe") (GL$) are under the control of two major histocompatibility-linked immune response (Ir) genes. One gene, termed lIrGLt-a, has been mappe to the IC or I-E subregion of the major histocompatibility complex, while the other, termed Ir-GL$-ft, has been mapped to the I-A subregion.In this paper we examine the effect of anti-I-region-associated (Ia) antisera on the T4ymphocyte proliferative response to GL$. Antibodies directed against Ia antigens coded for by genes in either the I-A or IC subregion were found to inhibit the proliferative response to GLU. These results suggest that a function mediated by two Ir gene products can be blocked by anti-Ia antisera directed against either one, and thus, that both products are expressed on the cell surface. We have previously demonstrated that in vitro antigen-induced proliferative responses of thymus-derived (T) lymphocytes can be inhibited by anti-Ia antisera (1). When the response being studied was under the control of specific immune response (Ir) genes, the anti-Ia inhibition showed haplotype specificity; that is, the proliferative response of T lymphocytes from primed (responder X nonresponder) F1 hybrids could only be blocked by antisera directed against Ia antigens coded for by the major histocompatibility complex (MHC) alleles of the responder parent. Furthermore, in instances in which an Ir gene had been mapped to a particular subregion of I, anti-Ia antisera specific for products of that subregion could inhibit activation. These results suggested an intimate relationship at the cell surface (or possibly in the culture supernatant) between Ia antigens and the molecules that mediate Ir gene function.We have also demonstrated that the immune response to poly(Glu53Lys36Phe11)n (GL4) is under the control of two MHC-linked Ir genes (2, 3). This requirement holds for both antibody formation (2) and T-lymphocyte proliferation (3). One gene, termed Ir-GL 4-a, was mapped to the I-C or I-E subregion of the MHC, and the other gene, termed Ir-GL4l-3, was mapped to the I-A subregion (4). In order to assess the relative functions of both gene products and, in particular, to ascertain whether both products had to function on the cell surface for activation to occur, it was of interest to determine the effect of anti-Ia antisera on the GL4-induced proliferative response.Because the two genes controlling the GLUE response are located in different subregions of the MHC, it was possible to selectively test the inhibitory effect of anti-Ia antisera directed against the products of each subregion. The experiments presented in this MATERIALS AND METHODS Animals. BALB/cAnN mice were obtained from the Division of Research Services, National Institutes of Health.B1O.D2/nSn, C57BL/lOSn (B10), A/J, and BlO.A(5R)/SgSn mice were purchased from the Jackson Laboratory, Bar Harbor, ME. The recombinant strains A.TH/SF, A.TL/SF, B1O.HTT/SF, BIO.S(9R)/Sg, D2.GD, an...

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Two genes in the major histocompatibility complex control immune response

Cited by 276 publications

References 20 publications

Regulatory mechanisms in cell-mediated immune responses. IV. Expression of a receptor for mixed lymphocyte reaction suppressor factor on activated T lymphocytes.

Regulatory mechanisms in cell-mediated immune responses. IV. Expression of a receptor for mixed lymphocyte reaction suppressor factor on activated T lymphocytes.

Genetic control of specific immune suppression. II. H-2-linked dominant genetic control of immune suppression by the random copolymer L-glutamic acid50-L-tyrosine50 (GT).

Inhibition of dual Ir gene-controlled T-lymphocyte proliferative response to poly (Glu56Lys35Phe9)n with anti-Ia antisera directed against products of either I-A or I-C subregion.

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