STAT3 in CD4+ T helper cell differentiation and inflammatory diseases

Abstract

Jak/STAT pathways influence cell-fate decisions made by differentiating naïve T cells, regulate the intensity and duration of inflammatory responses and are implicated in pathogenic mechanisms of a number of chronic inflammatory diseases. Among the STATs, the STAT3 protein has emerged as an important determinant of whether the naïve T cell differentiates into regulatory (Treg) or an inflammatory (Th17) T cell lineage. STAT3 also has potent anti-inflammatory effects and regulates critical cellular processes such as, cell growth, apoptosis and transcription of inflammatory genes. Dysregulation of STAT3 pathway has therefore been implicated in the development of chronic inflammatory diseases, as well as, a number of malignant and neurodegenerative diseases. This review focuses on recent findings regarding the role of STAT3 in immunity, with particular emphasis on T cell lineage specification and disease etiology. New insights from animal models of uveitis, multiple sclerosis and inflammatory bowel diseases are discussed as exemplars of critical roles that STAT3 pathways play in inflammatory diseases and on how inhibiting STAT3 can be exploited to mitigate pathogenic autoimmunity.

Figure 1

Structure of STAT3 protein. Similar to other members of the STAT family, STAT3 is comprised of six domains: N-terminal domain, coiled coil domain, DNA binding domain, linker domain, SH2 domain and Tran activation domain.

Figure 2

Outline of T-helper-cell differentiation. During the initial activation of CD4+ lymphocyte, the antigen presenting dendritic cells secrete a variety of cytokines that instruct the naïve T cell to activate one of several alternative T helper cell developmental pathways leading to Th1, Th2, Th17 or Treg lineage. Each T helper phenotype produces its signature cytokines that mediate its distinct immunoregulatory functions.

Figure 3

STAT3 at the nexus of Th17/Treg developmental programs. Differentiation into Th17 or inducible regulatory T cell (iTreg) lineage has an obligatory requirement for signals provided by TGF-β. Shortly after the activation of naive CD4⁺ T cells, convergence of IL-2 and TGF-β1 signals generates the common Treg/Th17 precursor characterized by expression of Foxp3 and ROR-γt. Further stimulation by TGF-β1 favors iTreg differentiation while maturation of the Treg/Th17 precursor in inflammatory niche with high levels of IL-6, inhibits Foxp3 and skews development towards Th17 phenotype. The Th17 master transcription factors, RORγt and RORα, induce expression of IL-23 receptor through STAT3-dependent mechanisms, rendering the differentiating Th17 cells responsive to IL-23, a cytokine essential for survival and stabilization of the Th17 phenotype. Sustained signaling through the IL-23 receptor might be required for the establishment of terminally differentiated Th17 effector phenotype.

Figure 4

Regulation of STAT3 signal transduction pathway. Cytokine binding induces receptor oligomerization that facilitate cross-phosphorylation and activation of the receptor-associated JAK kinases. Recruitment of STAT3 to activated gp130 receptors in response to cytokines result in their activation, dimerization and translocate into the nucleus to induce the expression of cytokine responsive genes including SOCS3 and to a lesser extent, SOCS1. The SOCS proteins inhibit or terminate JAK/STAT signals by binding to the activation loop tyrosine residues of JAKs and/or the tyrosine-phosphorylated cytokine receptors and target them for degradation by the proteosome. The STAT3 signal can also be attenuated by PIAS3, a member of the protein inhibitors of activated STATs (PIAS) family of proteins. PIAS3 binds selectively to activated STAT3 dimers and blocks their ability to bind DNA and activate transcription.