Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages

Helper T cells control host defense against pathogens. The receptors for interleukin 12 (IL-12), IL-4 and IL-6 are required for differentiation into the T(H)1, T(H)2 and T(H)17 subsets of helper T cells, respectively. IL-2 signaling via the transcription factor STAT5 controls T(H)2 differentiation by regulating both the T(H)2 cytokine gene cluster and expression of Il4ra, the gene encoding the IL-4 receptor a-chain. Here we show that IL-2 regulated T(H)1 differentiation, inducing STAT5-dependent expression of the IL-12 receptor beta 2-chain (IL-12R beta 2) and the transcription factor T-bet, 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 was restored by IL-12Rb2 expression. Consistent with the inhibition of T(H)17 differentiation by IL-2, treatment with IL-2 resulted in lower expression of the genes encoding the IL-6 receptor a-chain (Il6ra) and the IL-6 signal transducer gp130 (encoded by Il6st), and retroviral transduction of Il6st augmented T(H)17 differentiation even when IL-2 was present. Thus, IL-2 influences helper T cell differentiation by modulating the expression of cytokine receptors to help specify and maintain differentiated states.