Activation and Functional Specialization of Regulatory T Cells Lead to the Generation of Foxp3 Instability

Abstract

Accumulating evidence suggests that Foxp3 cells can downregulate the expression of Foxp3, but whether thymically derived regulatory T cells (tTregs; especially committed tTregs) are capable of downregulating Foxp3 expression and being reprogrammed into other T effector cells remains controversial. Using a novel tTreg lineage-tracing mouse line, we were able to label epigenetically stable Foxp3 cells derived from the thymus and demonstrate that mature tTregs are stable under homeostatic conditions. However, TCR engagement and sequential functional specialization of tTregs led to the generation of Foxp3 instability and reprogramming into the Th lineage. We further demonstrated that the signal switch from IL-2 to ICOS during Treg activation induced Treg instability and reprogramming. By using a dual lineage tracing model, we demonstrated that effector Tregs can revert to central Tregs, and this reversion is associated with increasing Foxp3 stability in vivo.

Filaggrin null mutations are associated with altered circulating Tregs in atopic dermatitis

“…Thymus‐derived Tregs are stable under homoeostatic conditions but can differentiate into Th‐like Tregs under inflammatory conditions . Yet, despite a fully demethylated Treg‐specific demethylated region (TSDR), thymus‐derived Tregs can re‐differentiate into Th cells and express proinflammatory cytokines, especially in inflammatory diseases that they might, in turn, exacerbate.…”

“…This suggests that the stability of FOXP3 expression in Tregs is not linked to and does not promote cell survival . Furthermore, expression of ICOS by Tregs can generate instability and reprogramming through the PI3K/AKT pathway, which, in turn, is detrimental to their suppression activity . Thus, ICOS + Treg viability may be impaired upon restimulation in patients with AD, hence impeding their production of IL‐10 and, in turn, the efficacy of their immunosuppression.…”

“…Thymus‐derived Tregs are increased in a mouse model of AD, similar to other inflammatory disorders . Interestingly, these cells can redifferentiate into Th‐like cells under inflammatory conditions . Moreover, restimulation of CCR6 – Tregs from AD patients with staphylococcal enterotoxin B enhances their production of IL‐5 and dampens that of IL‐10 .…”

Treg programming and therapeutic reprogramming in cancer

“…After activation, Tregs differentiate to suppress specific types of inflammation by expressing the same polarizing transcription factors, such as T‐bet, GATA3 or ROR‐ γ t, and the accompanying chemokine receptors to home to the same niche as the T‐cells they will control . The co‐expression of Foxp3 with transcription factors that control effector T‐cell functions may provide better precision for Treg immunosuppression but, also, competition between opposing T‐cell programmes can disrupt the immunosuppressive function of Tregs or the maintenance of Foxp3 expression itself . While it is not clear whether there is a common pattern of TI‐Treg differentiation in all cancers, selectively targeting specific subsets of TI‐Tregs based on chemokine receptor expression is an active area of investigation for the treatment of cancer.…”

“…[8][9][10] Treg activation within the TME leads to the induction of a repertoire of suppressive molecules, such as CTLA-4, GITR, PD-1 and LAG-3, which control antitumour immune responses. However, the activation of Tregs can also drive the destabilization of Foxp3 expression and induce the production of pro-inflammatory cytokines, [11][12][13] revealing that maintenance of Treg identity is tenuous during activation. Treg activation within the context of the TME also imparts a unique transcriptional programme that distinguishes TI-Tregs from Tregs present in normal tissues, indicating that Treg differentiation may adapt within cancers.…”