Differential Regulation of Transcription Factor T-Bet Induction During NK Cell Development and Th1 Cell Differentiation

Adaptive CD4 T helper cells and their innate counterparts, innate lymphoid cells, utilize an identical set of lineage-determining transcription factors (LDTFs) for their differentiation and functions. However, similarities and differences in the induction of LDTFs in these lymphocytes are still elusive. Here we show that type 1 T helper (Th1) cells and natural killer (NK) cells displayed distinct epigenomes at the Tbx21 locus, which encodes T-bet, the LDTF for type 1 lymphocytes. The initial induction of T-bet in NK precursors was dependent on the NK-specific DNase I hypersensitive site Tbx21-CNS-3 and the expression of IL-18 receptor; IL-18 induced T-bet expression through RUNX3, which bound to Tbx21-CNS-3 . By contrast, STAT-binding motifs within Tbx21-CNS-12 were critical for IL-12-induced T-bet expression during Th1 cell differentiation both in vitro and in vivo . Thus, type 1 innate and adaptive lymphocytes utilize distinct enhancer elements for their development and differentiation.