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

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Abstract
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-2kbmB- in H-2k/k TCR tg mice (in a situation of exclusive positive selection), peripheral tg TCR expressing (TI+) CDS+ T cells showed high, suboptimal, and an absence of reactivity for H-2Kb, H-2Kbm1, and H-2Kbms, respectively. In the peripheral lymphold organs of TCR tg H-2k/k, H-2k/bms, 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/bm1and H-2k/bms. This suggests that a week interaction between the TCR and H-2Kbms exists which partially results in negative, but not in positive, intrathymic selection. Results further indicate that expression of H-2Kbms does not induce tolerance to H-2Kb. In H-2k/bm1 mice, the peripheral TI+ CD810 cells express two distinct types of ‘threshold’ tolerance in vitro: (i) they generate cytoxic T lymphocytes (CTL), in the presence of exogenous IL-2, which fall to respond to H-2Kbm1 but remain reactive to H-2Kb; and (i) they do not make significant tlters 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+ CDB+ cells in response to H-2Kb were strongly affected in H-2k/bm1 mice. Thus in H-2k/kmice the TI+ CDB+ cells behave as helper-independent, whereas in H-2k/bm1 mice CD8+ cells expressing the same TCR behave as helper-dependent CTL.

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