title: Valpha24-JalphaQ-independent, CD1d-restricted recognition of alpha-galactosylceramide by human CD4(+) and CD8alphabeta(+) T lymphocytes.
abstract: Human CD1d molecules present an unknown ligand, mimicked by the synthetic glycosphingolipid alpha-galactosylceramide (alphaGC), to a highly conserved NKT cell subset expressing an invariant TCR Valpha24-JalphaQ paired with Vbeta11 chain (Valpha24(+)Vbeta11(+) invariant NK T cell (NKT(inv))). The developmental pathway of Valpha24(+)Vbeta11(+)NKT(inv) is still unclear, but recent studies in mice were consistent with a TCR instructive, rather than a stochastic, model of differentiation. Using CD1d-alphaGC-tetramers, we demonstrate that in humans, TCR variable domains other than Valpha24 and Vbeta11 can mediate specific recognition of CD1d-alphaGC. In contrast to Valpha24(+)Vbeta11(+)NKT(inv) cells, Valpha24(-)/CD1d-alphaGC-specific T cells express either CD8alphabeta or CD4 molecules, but they are never CD4 CD8 double negative. We show that CD8alphabeta(+)Valpha24(-)/CD1d-alphaGC-specific T cells exhibit CD8-dependent specific cytotoxicity and have lower affinity TCRs than Valpha24(+)/CD1d-alphaGC-specific T cells. In conclusion, our results demonstrate that, contrary to the currently held view, recognition of CD1d-alphaGC complex in humans is not uniformly restricted to the Valpha24-JalphaQ/Vbeta11 NKT cell subset, but can be mediated by a diverse range of Valpha and Vbeta domains. The existence of a diverse repertoire of CD1d-alphaGC-specific T cells in humans strongly supports their Ag-driven selection.
authors.affiliation: Nuffield Department of Clinical Medicine, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom. stephan.gadola@insel.ch
authors.forename: Stephan D
authors.initials: SD
authors.lastname: Gadola
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dulphy
authors.forename: Mariolina
authors.initials: M
authors.lastname: Salio
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
mesh_terms: D018949:Antigens, CD1 / Q000276:immunology*; D055610:Antigens, CD1d; D000954:Antigens, Surface / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005699:Galactosylceramides / Q000276:immunology*; D006801:Humans; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis / Q000502:physiology*
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; D000954:Antigens, Surface; C526877:CD1D protein, human; D005699:Galactosylceramides; C527203:KLRB1 protein, human; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D016693:Receptors, Antigen, T-Cell, alpha-beta