Treg functional stability and its responsiveness to the microenvironment

Abstract

Regulatory T cells (Tregs) prevent autoimmunity and tissue damage resulting from excessive or unnecessary immune activation through their suppressive function. While their importance for proper immune control is undeniable, the stability of the Treg lineage has recently become a controversial topic. Many reports have shown dramatic loss of the signature Treg transcription factor Forkhead box protein 3 (Foxp3) and Treg function under various inflammatory conditions. Other recent studies demonstrate that most Tregs are extremely resilient in their expression of Foxp3 and the retention of suppressive function. While this debate is unlikely to be settled in the immediate future, improved understanding of the considerable heterogeneity within the Foxp3(+) Treg population and how Treg subsets respond to ranging environmental cues may be keys to reconciliation. In this review, we discuss the diverse mechanisms responsible for the observed stability or instability of Foxp3(+) Treg identity and function. These include transcriptional and epigenetic programs, transcript targeting, and posttranslational modifications that appear responsive to numerous elements of the microenvironment. These mechanisms for Treg functional modulation add to the discussion of Treg stability.

Keywords: Foxp3; Treg; functional stability; proinflammatory cytokines.

Fig 1. Factors contributing to Treg functional instability

A variety of external inputs can disrupt Foxp3⁺ Treg function. This can occur through the disabling of Foxp3 through dephosphorylation or deacetylation or by WNT signaling. Also the Foxp3 protein pool can be targeted for degradation through ubiquitination and STAT3 signaling and high activity in the mTOR/AKT/PI3K pathway can also undermine Treg-associated gene regulation.

Fig 2. Factors contributing to Treg functional stability

An intrinsic epigenetic blueprint for Treg-mediated gene regulation imparts a high degree of stability to some Foxp3⁺ Tregs. Stable Treg function/gene expression may also be ensured by a network of Foxp3 coregulator molecules. Nrp1-Sema4A interactions suppress AKT mediated sequestration of Foxo proteins. The destabilizing polyubiquitination of Foxp3 protein is counteracted by USP7. Also, metabolites IDO and atRA provide stabilize induce and stabilize Tregs as do cytokines such as IL-2 and TGFβ and microRNAs.