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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 alphabeta 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 alphabeta 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 alpha 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 publication

DOI

10.1073/pnas.0502309102

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

06/09/2005

Volume

102

Pages

12855 - 12860

Keywords

Animals, Antigen-Presenting Cells, Cell Line, Hemochromatosis Protein, Histocompatibility Antigens Class I, Humans, Membrane Proteins, Mice, Mice, Knockout, Receptors, Antigen, T-Cell, T-Lymphocytes, Cytotoxic