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

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 gamma c. Thus, SOCS3 has been considered a selective suppressor of gp130 family cytokines, but not gamma c cytokines. Considering that gamma c signaling induces SOCS3 expression in T cells, here we revisited the role of SOCS3 on gamma c 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 gamma c 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 gamma c family cytokine IL-2. Collectively, we report an underappreciated role for SOCS3 in suppressing gamma c cytokine signaling, effectively expanding its scope of target cytokines in T cell immunity.