Cytokines belonging to the common cytokine receptor γ-chain (gc) family include IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Members of this family signal through receptor complexes that contain the γc/IL-2 Rγ subunit. The γc subunit associates with different cytokine-specific receptor subunits to form unique heterodimeric receptors for IL-4, IL-7, IL-9, and IL-21, or associates with both IL-2/IL-15 Rβ and IL-2 Rα or IL-15 Rα to form heterotrimeric receptors for IL-2 or IL-15, respectively. γc family cytokines generally activate three major signaling pathways that promote cellular survival and proliferation, the PI 3-K-Akt pathway, the Ras-MAPK pathway, and the JAK-STAT pathway. Differences in the expression patterns of the cytokines or their unique receptor components, along with the activation of different STAT proteins may account for some of the distinct effects mediated by γc family cytokines.
Signaling by γc family cytokines plays a major role in regulating the development, survival, proliferation, differentiation and/or function of different immune cell types. The importance of the γc family cytokines for the establishment and maintenance of the immune system is emphasized by the fact that mutations in γc/IL-2 Rg are associated with a disease known as X-linked severe combined immunodeficiency (XSCID), which is characterized by the absence of T cells and natural killer (NK) cells, and the presence of non-functional B cells. Knockout studies in mice have demonstrated that the lack of T cell and NK cell development in this disease can be primarily attributed to the respective loss of IL-7 and IL-15 signaling, while the loss of IL-4, IL-7, and IL-21 signaling leads to defective B cell development (although IL-7 is not required for B cell development in humans). Several additional unique and overlapping effects of the γc family cytokines on different immune cell types have been documented. A number of these effects are highlighted on the following pages to demonstrate the central role that γc family cytokines play in controlling immune system functions. Understanding the unique and overlapping activities of these cytokines and how their signaling pathways can be regulated is important to harness the therapeutic potential of the common γ-chain family cytokines for cancer immunotherapy, allergic and autoimmune diseases, and immunodeficient disease states. For more information, please visit rndsystems.com/commongammachain.