Cytokine receptor modulation by interleukin-2 broadly regulates T helper cell lineage differentiation

T helper (T(H)) cells control host-defense to pathogens. The receptors for IL-12, IL-4, and IL-6 are required for T(H)1, T(H)2, and T(H)17 differentiation, respectively. IL-2 signaling via the transcription factor STAT5 controls T(H)2 differentiation by regulating the T(H)2 cytokine gene cluster and Il4ra expression. Here we show that IL-2 regulates T(H)1 differentiation, inducing STAT5-dependent IL-12Rβ2 and T-bet expression, with impaired human T(H)1 differentiation when IL-2 was blocked. T(H)1 differentiation was also impaired in mouse Il2(−/−) T cells but restored by IL-12Rβ2 expression. Consistent with IL-2’s inhibition of T(H)17 differentiation, IL-2 decreased Il6ra and Il6st expression, and Il6st augmented T(H)17 differentiation even when IL-2 was present. Thus, IL-2 influences T(H) cell differentiation by modulating cytokine receptor expression to help specify and maintain differentiated states.