Transcriptional regulation of the NKT cell lineage

Abstract

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.

Figure 1. Thymic developmental pathway of the NKT cell lineage

The current model incorporates the newly discovered NKT2 and NKT17 subsets side by side with NKT1 cells (all of which correspond to developmental stage 3). The branching points between the NKT1, NKT2 and NKT17 sublineages at stage 1 and 2 are still under study. The thymic emigrants are still cycling and immature. Note, that Tbet⁺ NKT1 cells do produce IL4, albeit in smaller amounts than NKT2 cells. Some NKT1 precursors fail to emigrate, possibly due to premature downregulation of S1P₁ [67], and they accumulate in the thymus of aging mice (not depicted). NKR, NK lineage receptors including NK1.1, Ly49, NKG2D, CD94, DX5.