Loss of central and peripheral CD8+ T-cell tolerance to HFE in mouse models of human familial hemochromatosis. - Archive ouverte HAL Access content directly
Journal Articles European Journal of Immunology Year : 2012

Loss of central and peripheral CD8+ T-cell tolerance to HFE in mouse models of human familial hemochromatosis.

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François Huetz

Abstract

HFE, an MHC class Ib molecule that controls iron metabolism, can be directly targeted by cytotoxic TCR αβ T lymphocytes. Transgenic DBA/2 mice expressing, in a Rag 2 KO context, an αβ TCR that directly recognizes mouse HFE (mHFE) were created to further explore the interface of HFE with the immune system. TCR-transgenic mHfe WT mice deleted mHFE-reactive T cells in the thymus, but a fraction of reprogrammed cells were able to escape deletion. In contrast, TCR-transgenic mice deprived of mHFE molecules (mHfe KO mice) or expressing a C282→Y mutated mHFE molecule - the most frequent mutation associated with human hereditary hemochromatosis - positively selected mHFE-reactive CD8(+) T lymphocytes and were not tolerant toward mHFE. By engrafting these mice with DBA/2 WT (mHFE(+)) skin, it was established, as suspected on the basis of similar engraftments performed on DBA/2 mHfe KO mice, that mHFE behaves as an autonomous skin-associated histocompatibility antigen, even for mHFE-C282→Y mutated mice. By contrast, infusion of DBA/2 mHFE(+) mice with naïve mHFE-reactive transgenic CD8(+) T lymphocytes did not induce GVHD. Thus, tolerance toward HFE in mHfe WT mice can be acquired at either thymic or peripheral levels but is disrupted in mice reproducing human familial hemochromatosis.
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Dates and versions

inserm-00722713 , version 1 (03-08-2012)

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Cite

Rachid Boucherma, Hédia Kridane-Miledi, Francina Langa Vives, Charline Vauchy, Christophe Borg, et al.. Loss of central and peripheral CD8+ T-cell tolerance to HFE in mouse models of human familial hemochromatosis.. European Journal of Immunology, 2012, 42 (4), pp.851-62. ⟨10.1002/eji.201141664⟩. ⟨inserm-00722713⟩
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