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V24-JQ-Independent, CD1d-Restricted Recognition of -Galactosylceramide by Human CD4⁺ and CD8⁺ T Lymphocytes¹

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 -galactosylceramide (GC), to a highly conserved NKT cell subset expressing an invariant TCR V24-JQ paired with V11 chain (V24⁺V11⁺ invariant NK T cell (NKT^inv)). The developmental pathway of V24⁺V11⁺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-GC-tetramers, we demonstrate that in humans, TCR variable domains other than V24 and V11 can mediate specific recognition of CD1d-GC. In contrast to V24⁺V11⁺NKT^inv cells, V24^-/CD1d-GC-specific T cells express either CD8 or CD4 molecules, but they are never CD4 CD8 double negative. We show that CD8⁺V24^-/CD1d-GC-specific T cells exhibit CD8-dependent specific cytotoxicity and have lower affinity TCRs than V24⁺/CD1d-GC-specific T cells. In conclusion, our results demonstrate that, contrary to the currently held view, recognition of CD1d-GC complex in humans is not uniformly restricted to the V24-JQ/V11 NKT cell subset, but can be mediated by a diverse range of V and V domains. The existence of a diverse repertoire of CD1d-GC-specific T cells in humans strongly supports their Ag-driven selection.