Loss of central and peripheral CD8+ T-cell tolerance to HFE in mouse models of human familial hemochromatosis.
Fiche publication
Date publication
avril 2012
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BORG Christophe, Pr KLEINCLAUSS François
Tous les auteurs :
Boucherma R, Kridane-Miledi H, Vives FL, Vauchy C, Borg C, Kleinclauss F, Fiette L, Tiberghien P, Lemonnier FA, Rohrlich PS, Huetz F
Lien Pubmed
Résumé
HFE, an MHC class Ib molecule that controls iron metabolism, can be directly targeted by cytotoxic TCR alphabeta T lymphocytes. Transgenic DBA/2 mice expressing, in a Rag 2 KO context, an alphabeta 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 naive 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.
Référence
Eur J Immunol. 2012 Apr;42(4):851-62