Regulatory T cells in autoimmune disease

Abstract

In recent years, the understanding of regulatory T cell (T_reg cell) biology has expanded considerably. Key observations have challenged the traditional definition of T_reg cells and have provided insight into the underlying mechanisms responsible for the development of autoimmune diseases, with new therapeutic strategies that improve disease outcome. This Review summarizes the newer concepts of T_reg cell instability, T_reg cell plasticity and tissue-specific T_reg cells, and their relationship to autoimmunity. Those three main concepts have changed the understanding of T_reg cell biology: how they interact with other immune and non-immune cells; their functions in specific tissues; and the implications of this for the pathogenesis of autoimmune diseases.

Figure 1.. T_reg cell functional program in health and autoimmunity.

The T_reg cell functional program depends on two major axes: Foxp3 expression and a global epigenetic signature, both of which are regulated by a number of factors (gray boxes) and maintained under healthy conditions. In genetically susceptible individuals, environmental triggers induce inflammation, and a percentage of T_reg cells can lose Foxp3 expression and become unstable (T_reg cell instability, exFoxp3), or can maintain Foxp3 expression but alter their global epigenetic signature (T_reg cell plasticity), secrete pro-inflammatory cytokines and display reduced function. T_reg cell instability leads to the so-called ‘exFoxp3’ cells, which have been observed in mouse models of diabetes (NOD) and multiple sclerosis (EAE). T_reg cell plasticity favors the acquisition of T_H1-like, T_H2-like or T_H17-like properties by the T_reg cells, each of which have been observed in a number of autoimmune diseases in mice and humans. While the mechanistic connection between T_reg cell instability and plasticity is not known, plastic T_reg cells can become ‘normal’ T_reg cells after resolution of inflammation. It remains to be determined whether this is also the case for T_reg cell instability. Abbreviations: miRNA, microRNA; HACs, histone acetylases; HDACs, histone deacetylases; TF, transcription factors; NOD, non-obese diabetic; EAE, experimental autoimmune encephalomyelitis.