Direct recognition by αβ cytolytic T cells of Hfe, a MHC class Ib molecule without antigen-presenting function

Pierre S. Rohrlich, Nicolas Fazilleau, Florent Ginhoux, Hüseyin Firat, Frédérique Michels, Madeleine Cochet, Nihay Laham, Marie Paule Roth, Steve Pascolo, Faridabano Nato, Hélène Coppin, Pierre Charneau, Olivier Danos, Oreste Acuto, Rachel Ehrlich, Jean Kanellopoulos, François A. Lemonnier*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Crystallographic analysis of human Hfe has documented an overall structure similar to classical (class Ia) MHC molecules with a peptide binding groove deprived of ligand. Thus, to address the question of whether αβ T cells could recognize MHC molecules independently of bound ligands, we studied human and mouse Hfe interactions with T lymphocytes. We provide formal evidence of direct cytolytic recognition of human Hfe by mouse αβ T cell receptors (TCR) in HLA-A*0201 transgenic mice and that this interaction results in ZAP-70 phosphorylation. Furthermore, direct recognition of mouse Hfe molecules by cytotoxic T lymphocytes (CTLs) was demonstrated in DBA/2 Hfe knockout mice. These CTLs express predominantly two T cell antigen receptor α variable gene segments (AV6.1 and AV6.6). Interestingly, in wild-type mice we identified a subset of CD8+ T cells positively selected by Hfe that expresses the AV6.1/AV6.6 gene segments. T cell antigen receptor recognition of MHC molecules independently of bound ligand has potential general implications in alloreactivity and identifies in the Hfe case a cognitive link supporting the concept that the immune system could be involved in the control of iron metabolism.

Original languageEnglish
Pages (from-to)12855-12860
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number36
StatePublished - 6 Sep 2005


  • T cell receptor


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