A subset of NKT cells that lacks the NK1.1 marker, expresses CD1d molecules, and autopresents the alpha-galactosylceramide antigen

In the present report, we characterize a novel T cell subset that shares with the NKT cell lineage both CD1d-restriction and high reactivity in vivo and in vitro to the α-galactosylceramide (α-GalCer) glycolipid. These cells preferentially use the canonical Vα14-Jα281 TCR-α-chain and Vβ8 TCR-β segments, and are stimulated by α-GalCer in a CD1d-dependent fashion. However, in contrast to classical NKT cells, they lack the NK1.1 marker and express high surface levels of CD1d molecules. In addition, this NK1.1− CD1dhigh T subset, further referred to as CD1dhigh NKT cells, can be distinguished by its unique functional features. Although NK1.1+ NKT cells require exogenous CD1d-presenting cells to make them responsive to α-GalCer, CD1dhigh NKT cells can engage their own surface CD1d in an autocrine and/or paracrine manner. Furthermore, in response to α-GalCer, CD1dhigh NKT cells produce high amounts of IL-4 and moderate amounts of IFN-γ, a cytokine profile more consistent with a Th2-like phenotype rather than the Th0-like phenotype typical of NK1.1+ NKT cells. Our work reveals a far greater level of complexity within the NKT cell population than previously recognized and provides the first evidence for T cells that can be activated upon TCR ligation by CD1d-restricted recognition of their ligand in the absence of conventional APCs.