Regulatory T‐cell homeostasis: steady‐state maintenance and modulation during inflammation

Abstract

Summary Regulatory T (Treg) cells play a vital role in the prevention of autoimmunity and the maintenance of self-tolerance but also have an active role in inhibiting immune responses during viral, bacterial and parasitic infections. Whereas excessive Treg activity can lead to immunodeficiency, chronic infection and cancer, too little Treg activity results in autoimmunity and immunopathology, and impairs the quality of pathogen-specific responses. Recent studies have helped define the homeostatic mechanisms that support the diverse pool of peripheral Treg cells under steady-state conditions, and delineate how the abundance and function of Treg cells changes during inflammation. These findings are highly relevant for developing effective strategies to manipulate Treg cell activity to promote allograft tolerance and treat autoimmunity, chronic infection and cancer.

Flicr , a long noncoding RNA, modulates Foxp3 expression and autoimmunity

“…FoxP3 does not merely obey on/off regulation to dictate Treg repressive functions, but can be tuned in response to different environmental cues, particularly in conditions of limiting IL-2 (2,4,18,19). These results show that IL-2 has two means of enhancing Foxp3 expression, directly via activation of the Cns2 enhancer and indirectly by repressing Flicr, the attenuator of Foxp3.…”

“…by the transcription factor (TF) FoxP3, are fundamental actors in maintaining immune homeostasis, by dampening activation of several immunocyte lineages (1,2). In their absence, humans and mice develop devastating autoimmune and lymphoproliferative pathologies (3).…”

“…In their absence, humans and mice develop devastating autoimmune and lymphoproliferative pathologies (3). Although beneficial in preventing runaway immune activation, supporting tolerance of symbiotic microbes, and restraining tissue destruction in autoimmune lesions, their regulatory activity can also be deleterious, for example, by inhibiting antitumor (4) or antiviral responses (2,5).…”

“…This stability, and the stability of Foxp3 expression, result from a combination of factors (9): DNA hypomethylation at conserved enhancer elements of Foxp3 and other key loci (10) or selfreinforcing TF networks (11). This stability is bolstered by signals from IL-2, the key trophic cytokine for Tregs (2,7,9,12,13). At the center of this network lies FoxP3, the lineage-defining TF that is essential for Treg differentiation, maintenance, and function (1,(14)(15)(16)(17).…”

Unstable FoxP3 + T regulatory cells in NZW mice

“…Treg cells are under strong homeostatic control (11,12), perhaps made most evident for the rapid amplification that restores, in a matter of days, normal proportions of Treg cells after their acute ablation in mice (13,14). Cytokines-IL-2 foremost-are thought to be the main controllers of Treg proportions and numbers (15)(16)(17)(18)(19)(20)(21)(22), although the relative importance of these controllers varies with location and subphenotype [e.g., the alarmin IL-33 has a more profound role in tissue Tregs (21)(22)(23)].…”