Mechanisms of exTreg induction

Abstract

CD4⁺ CD25⁺ Foxp3⁺ Tregs play an important role in the maintenance of the immune system by regulating immune responses and resolving inflammation. Tregs exert their function by suppressing other immune cells and mediating peripheral self-tolerance. Under homeostatic conditions, Tregs are stable T-cell populations. However, under inflammatory environments, Tregs are converted to CD4⁺ CD25^low Foxp3^low cells. These cells are termed "exTreg" or "exFoxp3" cells. The molecular mechanism of Treg transition to exTregs remains incompletely understood. Uncertainties might be explained by a lack of consensus of biological markers to define Treg subsets in general and exTregs in particular. In this review, we summarize known markers of Tregs and factors responsible for exTreg generation including cytokines, signaling pathways, transcription factors, and epigenetic mechanisms. We also identify studies demonstrating the presence of exTregs in various diseases and sources of exTregs. Understanding the biology of Treg transition to exTregs will help in designing Treg-based therapeutic approaches.

Keywords: Regulatory T cells ⋅ exTregs ⋅ exFoxp3 ⋅ Treg plasticity ⋅ Treg stability.

Figure 1:. Mechanisms of exTreg generation.

Treg conversion to exTregs involves inhibition of CD25 and Foxp3 expression. The signaling pathways, transcription factors, and cytokines or chemokines, and their receptors that are involved in exTreg conversion are shown, along with factors responsible for the maintenance of Foxp3 stability in Tregs. (A) TCR activation induces PI3K/AKT/mTOR signaling which inhibits CD25 expression. mTOR induces proteasomal degradation of Foxp3 through E3 ubiquitin ligase Stub-1 and thus represses Foxp3/PTEN mediated inhibition of PI3K (73, 74). Foxp3 mediated upregulation of PTEN is important for Treg stability. (B) The anti-inflammatory factor DEL-1 binding to integrin receptor αvβ3 on Tregs induces heterodimerization of the transcription factors RUNX1-CBFβ. This heterodimer binds to the CNS2 region of the Foxp3 promoter to induce Foxp3 expression and inhibit Eomes transcription, thus preventing Eomes mediated Foxp3 suppression (66). (C) The proinflammatory cytokine IL-6 binds to its receptor, IL-6R, to induce JAK2/STAT3 signaling. IL-6 induces expression of DNMT3a, which binds to and induces methylation of the Foxp3 enhancer region, inhibiting Foxp3 expression. Transcription factor Blimp1 inhibits DNMT3a transcription and maintains Treg stability (103). (D) Alarmin IL-33 binds to its cognate receptor, ST2, induces GATA3 recruitment to the Foxp3 and St2 promoters, amplifying stable Foxp3 expression. IL-23 inhibits IL-33/ST2 signaling. Alarmin IL-1 inhibits Foxp3 expression via the mTORC1/HIF1α pathway (62). Created with BioRender.com.