Restoring self-tolerance in autoimmune diseases by enhancing regulatory T-cells

Abstract

Self-tolerance, the state of unresponsiveness to self-tissues/antigens, is maintained through central and peripheral tolerance mechanisms, and a breach of these mechanisms leads to autoimmune diseases. Foxp3 + T-regulatory cells (Tregs) play an essential role in suppressing autoimmune response directed against self-antigens and thereby regulate self-tolerance. Natural Tregs are differentiated in the thymus on the basis of their higher TCR-affinity to self-antigens and migrate to the periphery where they maintain peripheral tolerance. In addition, extra-thymic differentiation of induced Tregs can occur in the periphery which can control abrupt immune responses under inflammatory conditions. A defect in Treg cell numbers and/or function is found to be associated with the development of autoimmune disease in several experimental models and human autoimmune diseases. Moreover, augmentation of Tregs has been shown to be beneficial in treating autoimmunity in preclinical models, and Treg based cellular therapy has shown initial promise in clinical trials. However, emerging studies have identified an unstable subpopulation of Tregs which expresses pro-inflammatory cytokines under both homeostatic and autoimmune conditions, as well as in ex vivo cultures. In addition, clinical translation of Treg cellular therapy is impeded by limitations such as lack of easier methods for selective expansion of Tregs and higher cost associated with GMP-facilities required for cell sorting, ex vivo expansion and infusion of ex vivo expanded Tregs. Here, we discuss the recent advances in molecular mechanisms regulating Treg differentiation, Foxp3 expression and lineage stability, the role of Tregs in the prevention of various autoimmune diseases, and critically review their clinical utility for treating human autoimmune diseases.

Keywords: Autoimmunity; Foxp3 expression; Immune tolerance; Treg differentiation; Treg immunotherapy.

Figure-1:

Schematic diagram of transcriptional and epigenetic regulation of Foxp3 expression. Inducers of various transcription factors and respective transcription factor binding sites in the Foxp3 promoter and enhancer regions like CNS1, CNS2, and CNS3 are indicated using arrowheads. Effect of corresponding regions on tTreg and pTreg differentiation and function are also indicated.

Figure-2:

Schematic diagram of the mechanism of Treg functions. Different arms of Treg function such as CTLA4/TIGIT co-inhibition, CD39 mediated ATP deprivation, Perforin/granzyme-A and B mediated cytolysis, and immunosuppressive cytokines IL-10, IL-35, and TGF-β, and their target cell types are shown.