Control points in NKT-cell development

Natural killer T (NKT) cells are a developmentally and functionally distinct lineage of T cells restricted by CD1d–lipid antigen complexes. These cells branch from conventional MHC-restricted T cells at the CD4+CD8+ (double positive) stage of development in the thymus.NKT-cell selection requires an interaction between a randomly generated, semi-invariant (Vα14-Jα18+) T-cell receptor (TCR) and CD1d loaded with endogenous glycolipid antigen, expressed by CD4+CD8+ thymocytes that act as selecting cells. Isoglobo-trihexosylceramide (iGb3) is a mammalian glycolipid agonist ligand for NKT cells, and some studies suggest it has a key role in NKT-cell selection. However, other studies have challenged this view and further investigation is required to resolve the issue.Although the NKT-cell TCRα is invariant, a more diverse, yet still restricted range of randomly generated TCRβs can support NKT-cell selection. TCRβ contributes to the affinity of interaction with distinct glycolipid ligands and appears to endow the NKT-cell lineage with some flexibility in the types of antigen recognized.There are two crucial control points in NKT-cell development, both of which are CD1d dependent: control point 1 represents NKT-cell selection and occurs only in the thymus. Control point 2 can occur in the thymus or periphery and represents the functionally significant transition from an immature NK1.1− (CD161− in humans) phenotype to the mature NK1.1+ stage.The developmental relationships between subsets of functionally distinct mature NKT cells are not well understood. Known subsets include CD4+, CD4−CD8− and CD8+ (the CD8+ NKT-cell subset is present in humans but not mice) NKT cells, but others are likely to be discovered. CD4+ NKT cells seem to be the earliest NKT cells in mice and humans, but the point at which other subsets arise, and the factors that regulate these additional differentiation steps, are not known.A broad range of secreted and intracellular signalling factors have been identified that are selectively important for NKT-cell development, which supports the concept that NKT-cell differentiation is regulated independently of conventional T cells. These factors include interleukin-15 (IL-15), granulocyte/macrophage colony-stimulating factor (GM-CSF), lymphotoxin-α and lymphotoxin-β, nuclear factor-κB (NF-κB)-family members, SLAM (signalling lymphocytic activation molecule)-associated protein (SAP) and FYN.