The IL–10/STAT3 axis: Contributions to immune tolerance by thymus and peripherally derived regulatory T‐cells

Abstract

The signal transducer and activator of transcription (STAT) proteins are important mediators for the integration of extrinsic signals provided by cytokines and hormones and thereby adapt cellular processes to their surroundings. In the past decade, the involvement of STAT3 in the regulation of T-cell responses has become a topic of increasing interest. STAT3 is activated in response to multiple cytokines, many of which have been shown to influence T-cell responses. Interestingly, many of these factors have been described with apparent opposing roles, such as the highly pro-inflammatory potency of IL-6 and the anti-inflammatory properties of IL-10, thus raising the possibility that STAT3 signaling may fulfill diverse roles in CD4 + T-cells. Here, we review the contribution of STAT3 to the induction and function of both peripherally induced as well as thymus-derived regulatory T-cells. Indeed, experimental approaches as well as studies of human patients suffering from e.g. Job's (hyper IgE) syndrome or inflammatory bowel disease (IBD) have now established a clear-cut role for the IL-10/STAT3 axis in immune tolerance; further understanding of these processes could lead to novel therapeutic approaches for autoimmune diseases.Keywords: IL-10 r Regulatory T-cells r STAT3 r Tolerance r Tr1 cells IntroductionThe immune system evolved to discriminate between self and nonself determinants, maintaining homeostasis by recognizing and eliminating pathogenic microorganisms while sparing all the constituents of our own body [1]. It is an explicitly delicate task, on the one hand, to precisely recognize foreign invaders but, on the other hand, to strictly prevent autoimmunity to self-antigens. Apart from mechanisms deleting or anergizing lymphocytes expressing self-reactive antigen receptors centrally, i.e. at the level of thymic development for T-cells or during B-cell maturation Correspondence: Winfried F. Pickl e-mail: winfried.pickl@meduniwien.ac.at in the bone marrow and thus establishing central tolerance, several types of regulatory T-cells are also being generated in our body, both centrally and peripherally, contributing to the maintenance of immune tolerance [2,3]. In the past, transcription factors (TFs) driving specific T helper programs while inhibiting others have been described. Among them are TFs responsible for inducing Treg phenotype and function, such as the forkhead box protein 3, Foxp3, which nowadays is regarded as the master TF of thymus-derived Treg (tTreg) development during thymic T-cell maturation [4][5][6]. Moreover, recent discoveries in the authors' laboratory and others suggest that the TF signal transducer and activator of transcription 3, STAT3, seems to be critically involved in generating a hypo-responsive T-cell subtype [7], which shares, besides their hypo-responsiveness, several additional attributes with human T regulatory type 1 (Tr1) cells, such as elevated About IL-10 and STAT3Although initially described in T-cells, IL-10 is also produced by a large number of other immune cell types, ...

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