The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

The common cytokine receptor γ chain, γc, is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding γc results in X-linked severe combined immunodeficiency in humans, and γc family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications. The γc family of cytokines control development, growth, survival, and differentiation of immune cells. Leonard, O’Shea, and Lin review the diverse functions of this cytokine family and the clinical interventions that leverage the growing understanding of their complex biology for the treatment of disease.