Cytokine Signaling in the Development and Homeostasis of Regulatory T cells

Abstract

Cytokine signaling is indispensable for regulatory T-cell (Treg) development in the thymus, and also influences the homeostasis, phenotypic diversity, and function of Tregs in the periphery. Because Tregs are required for establishment and maintenance of immunological self-tolerance, investigating the role of cytokines in Treg biology carries therapeutic potential in the context of autoimmune disease. This review discusses the potent and diverse influences of interleukin (IL)-2 signaling on the Treg compartment, an area of knowledge that has led to the use of low-dose IL-2 as a therapy to reregulate autoaggressive immune responses. Evidence suggesting Treg-specific impacts of the cytokines transforming growth factor β (TGF-β), IL-7, thymic stromal lymphopoietin (TSLP), IL-15, and IL-33 is also presented. Finally, we consider the technical challenges and knowledge limitations that must be overcome to bring other cytokine-based, Treg-targeted therapies into clinical use.

Figure 1.

Cytokine contributions to regulatory T-cell (Treg) maturation in the thymus. Tregs develop from CD4 single-positive (SP) thymocyte precursors. Signaling through a high-affinity, self-reactive T-cell receptor (TCR) combined with CD28 costimulation is thought to trigger up-regulation of CD25. This potentiates the ability of Treg precursors to respond to interleukin (IL)-2, which prevents apoptosis, induces Foxp3 expression, and establishes Treg transcriptional identity and suppressive capacity. Boxes with dotted lines denote developmental stages where other cytokines may act. Dotted arrows denote a possible parallel pathway of Treg development. TGF-β, Transforming growth factor β.

Figure 2.

Effects of cytokine signaling on regulatory T cells (Tregs) in peripheral tissue sites. IL, Interleukin; TGF-β, transforming growth factor β; TSLP, thymic stromal lymphopoietin; LN, lymph node; Tconv, T conventional cell.