Threshold tolerance in H-2Kb-specific TCR transgenic mice expressing mutant H-2Kb: conversion of helper-independent to helper-dependent CTL.

To evaluate the role of the structure of the class I molecule and associated peptide(s) in intrathymic selection and tolerance, mice expressing as a transgene (tg) a TCR specific for the H-2Kb alloantigen were crossed with mice expressing the mutant class I molecule H-2Kbm1 or H-2Kbm8. In H-2k/k TCR tg mice (in a situation of exclusive positive selection), peripheral tg TCR expressing (Ti+) CD8+ T cells showed high, suboptimal, and an absence of reactivity for H-2Kb, H-2Kbm1, and H-2Kbm8, respectively. In the peripheral lymphoid organs of TCR tg H-2k/k, H-2k/bm8, H-2k/bm1, and H-2k/b mice respectively, the tg TCR was expressed on T cells with decreasing intensity of surface CD8. Thymic subpopulations of TCR tg mice presented a pattern of negative selection with decreasing intensity from H-2k/b to H-2k/bm1 and H-2k/bm8. This suggests that a weak interaction between the TCR and H-2Kbm8 exists which partially results in negative, but not in positive, intrathymic selection. Results further indicate that expression of H-2Kbm8 does not induce tolerance to H-2Kb. In H-2k/bm1 mice, the peripheral Ti+ CD8lo cells express two distinct types of 'threshold' tolerance in vitro: (i) they generate cytotoxic T lymphocytes (CTL), in the presence of exogenous IL-2, which fail to respond to H-2Kbm1 but remain reactive to H-2Kb; and (ii) they do not make significant titers of IL-2 and do not significantly proliferate in response to H-2Kb, unlike the Ti+ CD8+ T cells from H-2k/k TCR tg mice which respond efficiently. These results show that tolerance is induced up to a level of non-reactivity within a given MHC environment: for the same TCR, CTL reactivity to H-2Kbm1 is totally lost, whereas CTL reactivity to H-2Kb is only slightly reduced. Additionally, proliferation and IL-2 production by Ti+ CD8+ cells in response to H-2Kb were strongly affected in H-2k/bm1 mice. Thus, in H-2k/k mice the Ti+ CD8+ cells behave as helper-independent, whereas in H-2k/bm1 mice CD8+ cells expressing the same TCR behave as helper-dependent CTL.

[1]  T. Schumacher,et al.  A viral peptide can mimic an endogenous peptide for allorecognition of a major histocompatibility complex class I product , 1992, European journal of immunology.

[2]  A. Wakeham,et al.  Profound block in thymocyte development in mice lacking p56lck , 1992, Nature.

[3]  G. Schönrich,et al.  Influence of antigen density on degree of clonal deletion in T cell receptor transgenic mice. , 1992, International immunology.

[4]  D. Margulies,et al.  CD8 expression alters the fine specificity of an alloreactive MHC class I-specific T hybridoma. , 1992, International immunology.

[5]  E. Lacy,et al.  CD8 surface levels alter the fate of alpha/beta T cell receptor- expressing thymocytes in transgenic mice , 1992, The Journal of experimental medicine.

[6]  S. Nathenson,et al.  The structure of the antigen-binding groove of major histocompatibility complex class I molecules determines specific selection of self-peptides. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[7]  B. Rocha,et al.  An unusual lineage of alpha/beta T cells that contains autoreactive cells , 1991, The Journal of experimental medicine.

[8]  G. Morahan,et al.  A Transgenic Approach to the Study of Peripheral T‐Cell Tolerance , 1991, Immunological reviews.

[9]  L. Sherman,et al.  Alloreactive T cells discriminate among a diverse set of endogenous peptides. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[10]  H. Pircher,et al.  Lower receptor avidity required for thymic clonal deletion than for effector T-cell function , 1991, Nature.

[11]  G. Schönrich,et al.  Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction , 1991, Cell.

[12]  A. Heimberger,et al.  Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. , 1990, Science.

[13]  I. Weissman,et al.  T cell receptor-mediated negative selection of autoreactive T lymphocyte precursors occurs after commitment to the CD4 or CD8 lineages , 1990, The Journal of experimental medicine.

[14]  H. Pircher,et al.  Distinct sequence of negative or positive selection implied by thymocyte T-cell receptor densities , 1990, Nature.

[15]  C. Nelson,et al.  Positive selection of transgenic receptor-bearing thymocytes by Kb antigen is altered by Kb mutations that involve peptide binding. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[16]  B. Malissen,et al.  A novel type of aberrant T cell receptor alpha-chain gene rearrangement. Implications for allelic exclusion and the V-J recombination process. , 1990, Journal of immunology.

[17]  J. Davoust,et al.  A signaling role for the cytoplasmic segment of the CD8 alpha chain detected under limiting stimulatory conditions. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[18]  David M. Kranz,et al.  Positive and negative selection of an antigen receptor on T cells in transgenic mice , 1988, Nature.

[19]  D. Wiley,et al.  Evidence that multiple residues on both the α-helices of the class I MHC molecule are simultaneously recognized by the T cell receptor , 1988, Cell.

[20]  H. Boehmer,et al.  Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes , 1988, Nature.

[21]  J. Gabert,et al.  Reconstitution of MHC class I specificity by transfer of the T cell receptor and Lyt-2 genes , 1987, Cell.

[22]  A. Singer,et al.  Recognition Requirements for the Activation, Differentiation and Function of T‐Helper Cells Specific for Class I MHC Alloantigens , 1987, Immunological reviews.

[23]  C. Boyer,et al.  Monoclonal antibodies against an H-2Kb-specific cytotoxic T cell clone detect several clone-specific molecules. , 1986, Journal of immunology.

[24]  C. Boyer,et al.  Analysis of T cell activation requirements with the use of alloantigens or an anti-clonotypic monoclonal antibody. , 1986, Journal of immunology.

[25]  F. Denizot,et al.  A rat anti-mouse T4 monoclonal antibody (H129.19) inhibits the proliferation of Ia-reactive T cell clones and delineates two phenotypically distinct (T4+, Lyt-2,3-, and T4-, Lyt-2,3+) subsets among anti-Ia cytolytic T cell clones. , 1984, Journal of immunology.

[26]  J. Davignon,et al.  Clonal analysis of H-2Kb + TNP recognition by T cells with the use of H-2Kbm mutants and H-2Kb-specific monoclonal antibodies. , 1983, Journal of immunology.

[27]  C. Rudd.  CD4, CD8 and the TCR-CD3 complex: a novel class of protein-tyrosine kinase receptor. , 1990, Immunology today.

[28]  A. Singer,et al.  Analysis of T-cell subsets in rejection of Kb mutant skin allografts differing at class I MHC , 1986, Nature.