The cytokine milieu in the interplay of pathogenic Th1/Th17 cells and regulatory T cells in autoimmune disease

Abstract

The propagation and regulation of an immune response is driven by a network of effector and regulatory T (Treg) cells. The interplay of effector T and Treg cells determines the direction of the immune response towards inflammation or its resolution in an autoimmune disease setting. In autoimmune diseases, this interplay shifts the balance in favor of the development of autoreactive effector T cells, resulting in inflammatory pathology. The objective of an effective therapeutic approach for autoimmune disease is to restore this balance. In this review, we describe the characteristics and development of pathogenic T helper 1 (Th1) and Th17 cells and the beneficial Treg cells in autoimmune diseases and the crucial roles of the cytokine milieu in influencing the balance of these T-cell subsets. Given the importance of cytokines, we discuss current immunotherapeutic strategies using cytokine or cytokine receptor antibodies for the treatment of autoimmune diseases.

Figure 1

Model for Th cell differentiation from naive CD4⁺ T cells. In the presence of IL-12, differentiation of naive CD4⁺ T cells into Th1 cells requires activation of the master regulator transcription factor T-bet through STAT1 and STAT4. Th1 cells produce IFN-γ and are involved in cell-mediated immunity against intracellular bacteria and viruses. IL-4 promotes the activation of STAT6 and GATA3, which are responsible for Th2 cell differentiation. Th2 cells are important in humoral immunity against parasites, an action that is mediated through their production of IL-4, IL-5 and IL-13. The combination of TGF-β and proinflammatory cytokines, such as IL-6 and IL-23, drives the differentiation of naive CD4⁺ T cells into IL-17-producing Th cells (Th17) through the regulation of STAT3 and RORγt. Th17 cells play a critical role in host protection against extracellular pathogens and in inflammatory autoimmune diseases. In addition, TGF-β can induce differentiation of naive CD4⁺ T cells into Foxp3⁺ Treg cells, which produce TGF-β and IL-10 and act as modulators of immune responses. APC, antigen-presenting cell; Foxp3⁺, forkhead box p3⁺; IFN, interferon; MHC–TCR, major histocompatibility complex–T-cell receptor; ROR, retinoid-related orphan receptor; TGF, transforming growth factor; Th, T helper; Treg, regulatory T.

Figure 2

Critical role of IL-7/IL-7R signaling in survival and expansion of differentiated Th17 cells. Th17 cell development is a dichotomous process that is regulated through a complex cytokine network. The differentiation of Th17 cells is mainly mediated by STAT3 signaling through cytokines such as IL-6, IL-21 and IL-23. There is dynamic expression of IL-7R on Th17 cells in the course of T-cell activation/differentiation. In the latter phase, where IL-7R is re-expressed, IL-7 is critically required to sustain survival and expansion of differentiated Th17 cells through STAT5 signaling. IL-7R antagonism renders differentiated Th17 cells susceptible to apoptosis through altered expression of the proapoptotic protein Bax and the antiapoptotic molecule Bcl-2. APC, antigen-presenting cell; IL-7R, IL-7 receptor; MHC–TCR, major histocompatibility complex–T-cell receptor; TGF, transforming growth factor; Th, T helper.