CD1d-restricted iNKT cells, the 'Swiss-Army knife' of the immune system

Abstract

Natural Killer T cells are a distinct lymphocyte lineage that regulates a broad range of immune responses. NKT cells recognize glycolipids presented by the non-classical MHC molecule CD1d. Structural insight into the TCR/glycolipid/CD1d tri-complex has revealed an unusual and unexpected mode of recognition. Recent studies have also identified some of the signaling events during NKT cell development that give NKT cells their innate phenotype. Pathogen-derived glycolipid antigens continue to be found, and new mechanisms of NKT cell activation have been described. Finally, NKT cells have been shown to be remarkably versatile in function during various immune responses. Whether these extensive functional capacities can be attributed to a single population sensitive to environmental cues or if functionally distinct NKT cell subpopulations exist remains unresolved.

Figure 1. Activated iNKT cells, the “Swiss-army knife” of the immune system.

(A) CD1d-restricted iNKT cells exert potent killing activity and promptly release an impressive array of cytokines and chemokines that (B) influence many other cells of the innate and adaptive immune systems. Several known mechanisms for iNKT cell activation by pathogens have been identified (C) Microorganisms containing CD1drestricted glycolipids (Sphingomonas, Borrelia) directly activate iNKT cells through TCR engagement, in the absence of co-stimulation. (D) Alternatively, LPS-positive bacteria (Salmonella) activate TLR4-expressing APCs through LPS and can indirectly induce iNKT cell activation through presentation of self-glycolipid(s) in conjunction with IL-12 co-stimulation, or (E) by an IL-12/IL-18-dependent, CD1d-independent mechanism. (F) Finally, intracellular pathogens may stimulate TLR7/9 to induce the presentation of CD1d-restricted self-glycolipid(s) to iNKT cells. In this setting, co-stimulation by IFN-α/β is required.