Cytokines that share the common cytokine receptor gamma chain: old ideas and new lessons (LL2-1)

Abstract

The common cytokine-receptor γ-chain, γc, is an essential component of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 and is mutated in humans with X-linked severe combined immunodeficiency. IL-7 regulates T-cell development, IL-15 controls NK-cell development, and IL-4 and IL-21 together regulate immunglobulin production, with IL-21 regulating BLIMP1 expression and terminal B-cell differentiation. Sharing γc provides a basis for shared actions, but γc-family cytokines also potentially compete for γc to help explain opposing actions. Some γc-family cytokines induce their own receptors (e.g., IL-2Rβ by IL-2 or IL-4Rα by IL-4), but cross-regulation, such as repression of IL-7Rα or induction of IL-4Rα by IL-2 also occur; the former might diminish survival signals to promote AICD or facilitate the contraction phase following expansion after viral infection, whereas the latter primes for Th2 differentiation. Indeed, chromatin immunoprecipitation coupled to genome-wide sequencing (ChIP-Seq) revealed STAT5 recruitment to the Il4r locus earlier than to the Il4 locus; correspondingly, TCR-induced IL-4Rα expression requires IL-2 but not IL-4, supporting the key role for IL-2. All γc-family cytokines activate STAT proteins. Strikingly, IL-21-induced regulation of BLIMP1 requires both STAT3 and IRF4, and ChIP-Seq revealed that this extends broadly to IL-21-induced genes, leading us to discover that IRF4, like STAT3, is required for follicular T-cell differentiation. Collectively, these findings reveal dynamic regulation of γc-family cytokine receptors, clarifying the basis for cooperative vs. competitive actions by γc-family cytokines. Additionally, they have expanded our understanding of IL-21-mediated gene regulation, revealing added levels of complexity in signaling by γc-family cytokines.