New insights into the regulation of T cells by gamma(c) family cytokines

Abstract

Common cytokine receptor gamma-chain (gamma(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 alphabeta T cells, gammadelta 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.

Figure 1. Receptors for γ_c family cytokines and TSLP

Shown are the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, and TSLP. IL-2 and IL-15 are the only two of these cytokines to have three receptor chains. These two cytokines share IL-2Rβ, whereas IL-7 and TSLP share TSLPR, and of the cytokines shown, only TSLP does not share γ_c. There are three classes of IL-2 receptors, binding IL-2 with low affinity (IL-2Rα alone), intermediate affinity (IL-2Rβ + γ_c), and high affinity (IL-2Rα + IL-2Rβ + γ_c); only the high affinity IL-2 receptor is shown in the figure. Each γ_c family cytokine activates JAK1 and JAK3, whereas TSLP was reported to not activate any JAK kinase,. The major STAT proteins activated by these cytokines are shown. STAT5 refers to both STAT5A and STAT5B.

Figure 2. Direct and indirect actions of γ_c cytokines and TSLP on T cell expansion, homeostasis, and differentiation

γ_c cytokines can directly influence the survival, activation, proliferation, and differentiation of T cells (see top half of the figure), as well as indirectly affecting these processes via actions on DCs, macrophages, and Treg cells (bottom half of the figure). Although IL-15 is a critical factor for memory CD8⁺ T cell homeostasis, it also is responsible for the recovery of naïve CD8⁺ T cells in lymphopenic conditions. In the absence of IL-7, IL-15 has major effects on the homeostasis of memory CD4⁺ T cells. Both IL-7 and TSLP are important for the survival of naïve T cells, with IL-7 playing the greater role. The action of TSLP on memory T cells has not been evaluated. IL-2, IL-4 and IL-21 are produced by activated T cells and play essential role in T cell differentiation. In addition, IL-2 and IL-15 can augment expansion of T cells upon antigen-stimulation.

Figure 3. Mechanisms of T cell regulation by Treg cells

Treg cells exhibit several mechanisms to suppress activation and expansion of conventional T cells. Treg cells modulate functions of APCs by inhibiting their maturation and blocking of MHC molecules and co-stimulatory molecules (CD80 and CD86) on the surface of APCs and thus attenuating interactions between APCs and T cells. Treg cells might have cytolytic effects on target T cells as well as on APCs. Treg cells suppress activation and proliferation of T cells by their secretion of inhibitory cytokines, such as TGFβ, IL-10, and IL-35 and by consumption of γ_c cytokines. Deprivation of γ_c cytokines induces expression of pro-apoptotic proteins and elevates apoptotic rate of conventional T cells.