Markers and makers of NKT17 cells

Invariant natural killer T (iNKT) cells are thymus-generated innate-like αβ T cells that undergo terminal differentiation in the thymus. Such a developmental pathway differs from that of conventional αβ T cells, which are generated in the thymus but complete their functional maturation in peripheral tissues. Multiple subsets of iNKT cells have been described, among which IL-17-producing iNKT cells are commonly referred to as NKT17 cells. IL-17 is considered a proinflammatory cytokine that can play both protective and pathogenic roles and has been implicated as a key regulatory factor in many disease settings. Akin to other iNKT subsets, NKT17 cells acquire their effector function during thymic development. However, the cellular mechanisms that drive NKT17 subset specification, and how iNKT cells in general acquire their effector function prior to antigen encounter, remain largely unknown. Considering that all iNKT cells express the canonical Vα14-Jα18 TCRα chain and all iNKT subsets display the same ligand specificity, i.e., glycolipid antigens in the context of the nonclassical MHC-I molecule CD1d, the conundrum is explaining how thymic NKT17 cell specification is determined. Mapping of the molecular circuitry of NKT17 cell differentiation, combined with the discovery of markers that identify NKT17 cells, has provided new insights into the developmental pathway of NKT17 cells. The current review aims to highlight recent advances in our understanding of thymic NKT17 cell development and to place these findings in the larger context of iNKT subset specification and differentiation.