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* Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, Madison, WI 53706;
Department of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA 02115;
Department of Chemistry, The Scripps Research Institute, La Jolla, Ca 92037; and
School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom
CD1d-restricted NKT cells use structurally conserved TCRs and recognize both self and foreign glycolipids, but the TCR features that determine these Ag specificities remain unclear. We investigated the TCR structures and lipid Ag recognition properties of five novel V
24-negative and 13 canonical V24-positive/V
11-positive human NKT cell clones generated using -galactosylceramide (-GalCer)-loaded CD1d tetramers. The V24-negative clones expressed V11 paired with V10, V2, or V3. Strikingly, their V-chains had highly conserved rearrangements to J18, resulting in CDR3 loop sequences that are nearly identical to those of canonical TCRs. V24-positive and V24-negative clones responded similarly to -GalCer and a closely related bacterial analog, suggesting that conservation of the CDR3 loop is sufficient for recognition of -GalCer despite CDR1 and CDR2 sequence variation. Unlike V24-positive clones, the V24-negative clones responded poorly to a glucose-linked glycolipid (-glucosylceramide), which correlated with their lack of a conserved CDR1 amino acid motif, suggesting that fine specificity for -linked glycosphingolipids is influenced by V-encoded TCR regions. V24-negative clones showed no response to isoglobotrihexosylceramide, indicating that recognition of this mammalian lipid is not required for selection of J18-positive TCRs that can recognize -GalCer. One -GalCer-reactive, V24-positive clone differed from the others in responding specifically to mammalian phospholipids, demonstrating that semi-invariant NKT TCRs have a capacity for private Ag specificities that are likely conferred by individual TCR -chain rearrangements. These results highlight the variation in Ag recognition among CD1d-restricted TCRs and suggest that TCR -chain elements contribute to -linked glycosphingolipid specificity, whereas TCR -chains can confer heterogeneous additional reactivities.
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