The contribution of transcription factor IRF1 to the interferon-γ-interleukin 12 signaling axis and T_H1 versus T_H-17 differentiation of CD4⁺ T cells

Interleukin-12 (IL-12) and interferon-γ (IFN-γ) drive T helper type 1 (T_H1) differentiation, but the mechanisms underlying the regulation of the complicated gene networks involved in this differentiation are not fully understood. Here we show that the IFN-γ-induced transcription factor IRF1 was essential in T_H1 differentiation by acting on Il12rb1, the gene encoding the IL-12 receptor β1 subunit (IL-12Rβ1). IRF1 directly interacted with and activated the Il12rb1 promoter in CD4⁺ T cells. Notably, the IRF1-dependent induction of IL-12Rβ1 was essential for IFN-γ-IL-12 signaling but was dispensable for IL-23-IL-17 signaling. Because both IL-12 and IL-23 bind to and transmit signals through IL-12Rβ1, our data suggest that distinct thresholds of IL-12Rβ1 expression are required for T_H1 versus T_H-17 differentiation.