The extended family of CD1d-restricted NKT cells: sifting through a mixed bag of TCRs, antigens, and functions

Natural killer T (NKT) cells comprise a family of specialized T cells that recognize lipid antigens presented by CD1d. Based on their T cell receptor (TCR) usage and antigen specificities, CD1d-restricted NKT cells have been divided into two main subsets: type I NKT cells that use a canonical invariant TCR alpha-chain and recognize alpha-galactosylceramide (alpha-GalCer), and type II NKT cells that use a more diverse alpha beta TCR repertoire and do not recognize alpha-GalCer. In addition, alpha-GalCer-reactive NKT cells that use non-canonical alpha beta TCRs and CD1d-restricted T cells that use gamma delta or delta/alpha beta TCRs have recently been identified, revealing further diversity among CD1d-restricted T cells. Importantly, in addition to their distinct antigen specificities, functional differences are beginning to emerge between the different members of the CD1d-restricted T cell family. In this review, while using type I NKT cells as comparison, we will focus on type II NKT cells and the other non-invariant CD1d-restricted T cell subsets, and discuss our current understanding of the antigens they recognize, the formation of stimulatory CD1d/antigen complexes, the modes of TCR-mediated antigen recognition, and the mechanisms and consequences of their activation that underlie their function in antimicrobial responses, anti-tumor immunity, and autoimmunity.