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24-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 V
11 chain (V24+V11+
invariant NK T cell (NKTinv)). The developmental pathway of
V24+V11+NKTinv 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+NKTinv 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.
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