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

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Abstract
IL-2 is well known for its effects on the proliferation of T cells. Leonard and colleagues demonstrate a mechanism in which IL-2 is critical for supporting TH1 differentiation but blocks TH17 differentiation. 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 TH1, TH2 and TH17 subsets of helper T cells, respectively. IL-2 signaling via the transcription factor STAT5 controls TH2 differentiation by regulating both the TH2 cytokine gene cluster and expression of Il4ra, the gene encoding the IL-4 receptor α-chain. Here we show that IL-2 regulated TH1 differentiation, inducing STAT5-dependent expression of the IL-12 receptor β2-chain (IL-12Rβ2) and the transcription factor T-bet, with impaired human TH1 differentiation when IL-2 was blocked. TH1 differentiation was also impaired in mouse Il2−/− T cells but was restored by IL-12Rβ2 expression. Consistent with the inhibition of TH17 differentiation by IL-2, treatment with IL-2 resulted in lower expression of the genes encoding the IL-6 receptor α-chain (Il6ra) and the IL-6 signal transducer gp130 (encoded by Il6st), and retroviral transduction of Il6st augmented TH17 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.