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, the similarities and differences in the induction of the 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 partially 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 binds to Tbx21-CNS-3. By contrast, Tbx21-CNS-12 containing STAT binding motifs was critical for IL-12-induced T-bet expression during Th1 cell differentiation both in vitro and in vivo. Thus, innate and adaptive lymphocytes of same class may utilize distinct enhancer elements for their development and differentiation. Naïve CD4 T cells were isolated from lymph node and cultured under Th1, Th2, or Th17 condition for DNase-seq or ChIP-seq using anti-T-bet antibodies. cNK cells and ILC1s were isolated from liver for DNase-seq. cNK cells were isolated from spleen for ChIP-seq using anti-T-bet antibodies. ILC2s and LTi cells were isolated from small intestine for DNase-seq.