On the road: progress in finding the unique pathway of invariant NKT cell differentiation

Two populations of natural killer T cells with invariant TCR α-chains (iNKT cells) have been identified in mice and humans. These conserved populations have distinct functional properties and anatomical distributions. The differentiation pathway of iNKT cells positively selected by CD1d molecules branches off from the pathway of mainstream thymocyte development at the double-positive (CD4+CD8+) stage. Recent work shows how signaling events early in the thymus can imprint the memory-like behavior of these iNKT cells and that unique molecular interactions govern their development and emigration from the thymus. Factors shaping their variable repertoire of the T-cell antigen receptor β-chain, in addition to novel autologous antigens, have been defined; however, it remains unclear whether there is a single autologous antigen responsible for both positive selection and peripheral activation.