New insights into the regulation of T cells by γc family cytokines

Abstract

The common cytokine receptor γ-chain (γ_c) family of cytokines consists of interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21, each of which is a short-chain four α-helical bundle type I cytokine. Mutations in the gene encoding γ_c (IL2RG) in humans result in X-linked severe combined immunodeficiency, which is characterized by a marked defect in the development of T and natural killer (NK) cells and functional defects of B cells; in mice, deletion of this gene is characterized by the absence of B, T and NK cells. γ_c family cytokines and the related cytokine thymic stromal lymphopoietin (TSLP) have distinct effects on the regulation of survival and proliferation of T cells. IL-2 and TSLP increase the proliferation and/or survival of effector T cells, whereas IL-7, IL-15 and TSLP are survival factors for naive and memory αβ T cells, as well as γδ T cells. In addition, the combination of IL-15 and IL-21 increases the proliferation and decreases the apoptosis of CD8⁺ T cells. As well as the direct effects of γ_c family cytokines and TSLP on the homeostasis of T cells, they also have indirect effects on T cells through their regulation of dendritic cell (DC) functions. IL-15 and TSLP induce the up-regulation of expression of co-stimulatory molecules and increased presentation of antigen on DCs, whereas IL-7 and IL-21 suppress the maturation of DCs. Although IL-2 is an important factor for the development and function of regulatory T (T_Reg) cells, the lack of IL-2, IL-2Rα or IL-2Rβ does not alter the expression of forkhead box P3 (FOXP3) or result in a complete loss of T_Reg cells. By contrast, STAT5 activation is sufficient to increase the number of CD4⁺CD25⁺ T_Reg cells even when IL-2-induced signalling is defective, which shows that STAT5A and STAT5B are crucial factors downstream of IL-2R and indicates that other factors that activate the STAT5 pathway might also contribute to T_Reg cell development and could partially compensate when IL-2-induced signalling is defective. Indeed, IL-7, IL-15 and TSLP also contribute to T_Reg cell development and function. In the primary response to antigen, naive CD4⁺ T cells differentiate to distinct polarized subsets, including T helper 1 (T_H1), T_H2, T_H17 and T follicular helper (T_FH) cells. Recent studies show that IL-2 and IL-4 are both required for the efficient induction of T_H2 cells and that IL-21 can promote the differentiation of T_H17 cells and T_FH cells. In addition to their contributions to T_H cell differentiation, γ_c cytokines also contribute to the generation and activity of cytotoxic CD8⁺ T cells, with IL-2, IL-15 and IL-21 increasing the cytolytic activity of CD8⁺ T cells during priming and increasing their antitumour immunity. The actions of γ_c cytokines have clinical relevance, and modulation of their effects has implications for the treatment of cancer, autoimmunity, allergy and immunodeficiency. Administration of IL-2, IL-15 and IL-21 has antitumour effects; treatment with IL-2, IL-7 and IL-15 could be used in immunodeficiency disorders; blocking of IL-4, IL-9 and TSLP can decrease allergic symptoms; and neutralization of IL-21 could prevent and/or ameliorate several autoimmune diseases.