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.
Auphan
N
N
Centre d'Immunologie INSERM-CNRS de Marseille-Luminy, France.
Jézo-Brémond
A
A
Schönrich
G
G
Hämmerling
G
G
Arnold
B
B
Malissen
B
B
Schmitt-Verhulst
A M
AM
D000818:Animals; D016827:CD8 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation; D002478:Cells, Cultured; D003433:Crosses, Genetic; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009154:Mutation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology
D016827:CD8 Antigens; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell