Direct recognition by alphabeta cytolytic T cells of Hfe, a MHC class Ib molecule without antigen-presenting function.
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.
Rohrlich
Pierre S
PS
Unité d'Immunité Cellulaire Antivirale, Département d'Immunologie, Institut Pasteur, 75724 Paris, France.
Fazilleau
Nicolas
N
Ginhoux
Florent
F
Firat
Hüseyin
H
Michel
Frédérique
F
Cochet
Madeleine
M
Laham
Nihay
N
Roth
Marie Paule
MP
Pascolo
Steve
S
Nato
Faridabano
F
Coppin
Hélène
H
Charneau
Pierre
P
Danos
Olivier
O
Acuto
Oreste
O
Ehrlich
Rachel
R
Kanellopoulos
Jean
J
Lemonnier
François A
FA
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D002460:Cell Line; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
C103673:HFE protein, human; D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell