Lineage Differentiation Program of Invariant Natural Killer T Cells

Invariant natural killer T (iNKT) cells are innate T cells restricted by CD1d molecules. They are positively selected in the thymic cortex and migrate to the medullary area, in which they differentiate into 3 different lineages. Promyelocytic leukemia zinc finger (PLZF) modulates this process, and PLZFhigh, PLZFintermediate, and PLZFlow iNKT cells are designated as NKT2, NKT17, and NKT1 cells, respectively. Analogous to conventional helper CD4 T cells, each subset expresses distinct combinations of transcription factors and produces different cytokines. In lymphoid organs, iNKT subsets have unique localizations, which determine their cytokine responses upon antigenic challenge. The lineage differentiation programs of iNKT cells are differentially regulated in various mice strains in a cell-intrinsic manner, and BALB/c mice contain a high frequency of NKT2 cells. In the thymic medulla, steady state IL-4 from NKT2 cells directly conditions CD8 T cells to become memory-like cells expressing Eomesodermin, which function as premade memory effectors. The genetic signature of iNKT cells is more similar to that of γδ T cells and innate lymphoid cells (ILCs) than of conventional helper T cells, suggesting that ILCs and innate T cells share common developmental programs.