Journal Article

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

Leonard, Warren J., Rochman, Yrina, Spolski, Rosanne

2009

Overview

Key Points 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 H 1), T H 2, T H 17 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 H 2 cells and that IL-21 can promote the differentiation of T H 17 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. In this Review, the authors discuss the central roles of the common cytokine receptor γ-chain (γ c ) family of cytokines, as well as the related cytokine TSLP, in the homeostasis, proliferation and differentiation of various T cell subsets and describe how these cytokines could be exploited for therapeutic purposes. Common cytokine receptor γ-chain (γ c ) family cytokines have crucial roles in the development, proliferation, survival and differentiation of multiple cell lineages of both the innate and adaptive immune systems. In this Review, we focus on our current understanding of the distinct and overlapping effects of interleukin-2 (IL-2), IL-7, IL-9, IL-15 and IL-21, as well as the IL-7-related cytokine thymic stromal lymphopoietin (TSLP), on the survival and proliferation of conventional αβ T cells, γδ T cells and regulatory T cells. This knowledge potentially allows for the therapeutic manipulation of immune responses for the treatment of cancer, autoimmunity, allergic diseases and immunodeficiency, as well as for vaccine development.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Allergies / Antigen presentation / Antigens / Antitumor activity / Apoptosis / Autoimmune diseases / Autoimmunity / Biomedical and Life Sciences / Biomedicine / CD4 antigen / Cell activation / Cell differentiation / Cell proliferation / Cell survival / Clonal deletion / Cytokines / Cytotoxicity / Dendritic cells / Helper cells / Homeostasis / Immune system / Immunological memory / Immunology / Interleukin 2 / Interleukin 2 receptors / Interleukin 4 / Interleukin 7 / Interleukin 9 / Lymphocytes / Lymphocytes B / Lymphocytes T / Neutralization / review-article / Signal transduction / Therapeutic applications / Thymus