Transcriptional regulation of the NKT cell lineage

How expression of canonical semi-invariant TCRs leads to innate-like effector differentiation is a central enigma of NKT cell development. NKT thymic precursors undergo elevated TCR signals leading to increased Egr2, which directly induces their signature transcription factor, PLZF. PLZF is necessary and sufficient to induce a multipotent, unbiased effector program that precedes terminal differentiation into T-bet(high) NK1.1(+) (NKT1) cells and recently identified NKT2 and NKT17 sublineages. Major variations in polarized NKT sublineages have been uncovered in different mouse strains and in several mutants, with direct impact on NKT cell function but also, unexpectedly, on the development and function of conventional T cells.