A semi-invariant Vα10+ T cell antigen receptor defines a population of natural killer T cells with distinct glycolipid antigen–recognition properties

Abstract

Type I natural killer T cells (NKT cells) are characterized by an invariant variable region 14–joining region 18 (Vα14-Vα18) T cell antigen receptor (TCR) α-chain and recognition of the glycolipid α-galactosylceramide (α-GalCer) restricted to the antigen-presenting molecule CD1d. Here we describe a population of α-GalCer-reactive NKT cells that expressed a canonical Vα10-Jα50 TCR α-chain, which showed a preference for α-glucosylceramide (α-GlcCer) and bacterial α-glucuronic acid–containing glycolipid antigens. Structurally, despite very limited TCRα sequence identity, the Vα10 TCR–CD1d–α-GlcCer complex had a docking mode similar to that of type I TCR–CD1d–α-GalCer complexes, although differences at the antigen-binding interface accounted for the altered antigen specificity. Our findings provide new insight into the structural basis and evolution of glycolipid antigen recognition and have notable implications for the scope and immunological role of glycolipid-specific T cell responses.

Vβ2 natural killer T cell antigen receptor-mediated recognition of CD1d-glycolipid antigen

“…Consequently, our data suggest that the Vα chain and specifically, the Jα18-encoded loop, which contacts CD1d and the Ag, drive the pattern recognition receptor properties of the NKT TCR (26). However, recent studies have also identified a population of α-GalCer-reactive semi-invariant NKT cells in which the TCR α-chain is comprised of the Vα10-Jα50 genes and the TCR β-chain is largely restricted to the Vβ8 and Vβ7 genes (23). Despite the markedly different sequences of the Jα18-and Jα50-encoded gene segments, the Vα10-Jα50 NKT TCR docked onto CD1d-Ag in a very similar manner to the docking of the Vα14-Jα18 NKT TCR-CD1d-Ag complexes.…”

“…Furthermore, the structures of NKT TCRs in complex with α-GalCer analogs as well as α-galactosyldiacylglycerol, the self-Ag phosphatidyl inositol, and some β-linked Ags have been determined (17)(18)(19)(20)(21)(22)(23). In all NKT TCR-CD1d-Ag complexes determined to date, a conserved, tilted, and parallel docking mode with respect to the CD1d Agbinding cleft was observed.…”

“…Such considerations have resonances with TCR-peptide-MHC (pMHC) recognition, where the CDR2β loop of Vβ8.2-containing TCRs is considered to define the basis for MHC bias for this slice of the T cell repertoire (28)(29)(30). In the context of what determines CD1d restriction, we recently showed the existence of a population of semi-invariant NKT cells that expresses a canonical Vα10-Jα50 TCR α-chain paired with either Vβ8 or Vβ7, which are also α-GalCer-reactive (23). Nevertheless, this Vα10 NKT TCR adopted the same docking mode to CD1d-Ag as the method observed for Type I NKT cells (23).…”

“…In the context of what determines CD1d restriction, we recently showed the existence of a population of semi-invariant NKT cells that expresses a canonical Vα10-Jα50 TCR α-chain paired with either Vβ8 or Vβ7, which are also α-GalCer-reactive (23). Nevertheless, this Vα10 NKT TCR adopted the same docking mode to CD1d-Ag as the method observed for Type I NKT cells (23). Given that a similar TCR β-chain bias was observed for these Vα10 NKT cells, this finding suggests a dominant role for the TCR β-chain in determining the conserved docking mode exhibited by NKT cells.…”

Recognition of microbial and mammalian phospholipid antigens by NKT cells with diverse TCRs

“…Although there is some hierarchy in affinity of different mouse iNKT cell TCRs based on TCR β-chain use (22,23), stimulation with iNKT cell antigens generally results in immediate, innate-like responses of the entire iNKT cell population. iNKT cells, and the recently described semi-invariant Vα10 + CD1d-restricted NKT cells, use a unique mode of TCR recognition of lipid/CD1d complexes in which recognition of the lipid antigen is mediated primarily by the semi-invariant TCR α-chain, and the TCR β-chain appears to only modulate affinity (24)(25)(26). In contrast, MHC-restricted T cells, as well as human CD1a-, b-, and c-restricted T cells, show a high degree of specificity for unique antigens and stimulation with their cognate antigens results in clonal expansion and adaptive T-cell responses (27).…”