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The Journal of Immunology, 2002, 168: 5514-5520.
Copyright © 2002 by The American Association of Immunologists

V{alpha}24-J{alpha}Q-Independent, CD1d-Restricted Recognition of {alpha}-Galactosylceramide by Human CD4+ and CD8{alpha}{beta}+ T Lymphocytes1

Stephan D. Gadola2, Nicolas Dulphy, Mariolina Salio and Vincenzo Cerundolo3

Nuffield Department of Clinical Medicine, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom

Human CD1d molecules present an unknown ligand, mimicked by the synthetic glycosphingolipid {alpha}-galactosylceramide ({alpha}GC), to a highly conserved NKT cell subset expressing an invariant TCR V{alpha}24-J{alpha}Q paired with V{beta}11 chain (V{alpha}24+V{beta}11+ invariant NK T cell (NKTinv)). The developmental pathway of V{alpha}24+V{beta}11+NKTinv is still unclear, but recent studies in mice were consistent with a TCR instructive, rather than a stochastic, model of differentiation. Using CD1d-{alpha}GC-tetramers, we demonstrate that in humans, TCR variable domains other than V{alpha}24 and V{beta}11 can mediate specific recognition of CD1d-{alpha}GC. In contrast to V{alpha}24+V{beta}11+NKTinv cells, V{alpha}24-/CD1d-{alpha}GC-specific T cells express either CD8{alpha}{beta} or CD4 molecules, but they are never CD4 CD8 double negative. We show that CD8{alpha}{beta}+V{alpha}24-/CD1d-{alpha}GC-specific T cells exhibit CD8-dependent specific cytotoxicity and have lower affinity TCRs than V{alpha}24+/CD1d-{alpha}GC-specific T cells. In conclusion, our results demonstrate that, contrary to the currently held view, recognition of CD1d-{alpha}GC complex in humans is not uniformly restricted to the V{alpha}24-J{alpha}Q/V{beta}11 NKT cell subset, but can be mediated by a diverse range of V{alpha} and V{beta} domains. The existence of a diverse repertoire of CD1d-{alpha}GC-specific T cells in humans strongly supports their Ag-driven selection.




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