SOCS3 is a suppressor of γc cytokine signaling and constrains generation of murine Foxp3 + regulatory T cells

Abstract SOCS3 is a cytosolic inhibitor of cytokine signaling that suppresses the activation of cytokine receptor‐associated JAK kinases. Mechanistically, SOCS3 is recruited to a site in the cytokine receptors known as the SOCS3‐interaction motif, and then binds JAK molecules to inhibit their kinase activity. The SOCS3‐interaction motif is found in receptors of the gp130 cytokine family but mostly absent from other cytokine receptors, including γc. Thus, SOCS3 has been considered a selective suppressor of gp130 family cytokines, but not γc cytokines. Considering that γc signaling induces SOCS3 expression in T cells, here we revisited the role of SOCS3 on γc signaling. Using SOCS3 transgenic mice, we found that increased abundance of SOCS3 not only suppressed signaling of the gp130 family cytokine IL‐6, but also signaling of the γc family cytokine IL‐7. Consequently, SOCS3 transgenic mice were impaired in IL‐7‐dependent T cell development in the thymus and the homeostasis of mature T cells in peripheral tissues. Moreover, enforced SOCS3 expression interfered with the generation of Foxp3 + regulatory T cells that requires signaling by the γc family cytokine IL‐2. Collectively, we report an underappreciated role for SOCS3 in suppressing γc cytokine signaling, effectively expanding its scope of target cytokines in T cell immunity.