Activated T Cells Secrete an Alternatively Spliced Form of Common γ-Chain that Inhibits Cytokine Signaling and Exacerbates Inflammation

Abstract

The common gamma-chain (gamma c) plays a central role in signaling by IL-2 and other gamma c-dependent cytokines. Here we report that activated T cells produce an alternatively spliced form of gc mRNA that results in protein expression and secretion of the gamma c extracellular domain. The soluble form of gamma c (s gamma c) is present in serum and directly binds to IL-2R beta and IL-7R alpha proteins on T cells to inhibit cytokine signaling and promote inflammation. s gamma c suppressed IL-7 signaling to impair naive T cell survival during homeostasis and exacerbated Th17-cell-mediated inflammation by inhibiting IL-2 signaling upon T cell activation. Reciprocally, the severity of Th17-cell-mediated inflammatory diseases was markedly diminished in mice lacking s gamma c. Thus, s gamma c expression is a naturally occurring immunomodulator that regulates gamma c cytokine signaling and controls T cell activation and differentiation.