T-bet is a STATI-induced regulator for IL-12R expression in naïve CD4⁺ T cells

T helper type I (T_H1) cell development involves interferon-γ (IFN-γ) signaling through signal transducer and activator of transcription I (STAT I) and interleukin-12 (IL-12) signaling through STAT4 activation. We examined here T-bet regulation and evaluated the actions of T-bet in STAT1- and STAT4-dependent T_H1 development processes. We found that T-bet expression during T cell activation was strongly dependent on IFN-γ signaling and STATI activation, but was independent of STAT4. Ectopic T-bet expression strongly increased IFN-γ production in T_H2 cells activated by PMA-ionomycin, but weakly increased IFN-γ production in T_H2 cells stimulated by IL-12-IL-18 or OVA peptide-antigen-presenting cell stimulation. In contrast, IL-12-IL-18-induced IFN-γ production remained STAT4-dependent despite ectopic T-bet expression. Ectopic T-bet expression selectively induced expression of IL-12Rβ2, but not IL-18Rα, in wild-type and STAT1^−/− T_H2 cells, but did not extinguish expression of GATA-3 and T_H2 cytokines. Finally, ectopic T-bet did not directly induce expression of endogenous T- bet independently of IFN-γ or STAT1. Thus, T-bet is induced by IFN-γ and STAT1 signaling during T cell activation. In addition, T-bet mediates STAT1-dependent processes of T_H1 development, including the induction of IL-12Rβ2.