The common γ-chain cytokine receptor: Tricks-and-treats for T cells

Abstract

Originally identified as the third subunit of the high-affinity IL-2 receptor complex, the common gamma-chain (gamma c) also acts as a non-redundant receptor subunit for a series of other cytokines, collectively known as gamma c family cytokines. gamma c plays essential roles in T cell development and differentiation, so that understanding the molecular basis of its signaling and regulation is a critical issue in T cell immunology. Unlike most other cytokine receptors, gamma c is thought to be constitutively expressed and limited in its function to the assembly of high-affinity cytokine receptors. Surprisingly, recent studies reported a series of findings that unseat gamma c as a simple housekeeping gene, and unveiled gamma c as a new regulatory molecule in T cell activation and differentiation. Cytokine-independent binding of gamma c to other cytokine receptor subunits suggested a pre-association model of gamma c with proprietary cytokine receptors. Also, identification of a gamma c splice isoform revealed expression of soluble gamma c proteins (s gamma c). s gamma c directly interacted with surface IL-2R beta to suppress IL-2 signaling and to promote pro-inflammatory Th17 cell differentiation. As a result, endogenously produced s gamma c exacerbated autoimmune inflammatory disease, while the removal of endogenous s gamma c significantly ameliorated disease outcome. These data provide new insights into the role of both membrane and soluble gamma c in cytokine signaling, and open new venues to interfere and modulate gamma c signaling during immune activation. These unexpected discoveries further underscore the perspective that gamma c biology remains largely uncharted territory that invites further exploration.