Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo

Abstract

Regulatory T (Treg) cells play a central role in maintaining immune homeostasis. However, little is known about the stability of Treg cells in vivo. In this study, we demonstrate that a significant percentage of cells exhibited transient or unstable Foxp3 expression. These exFoxp3+ T cells express an activated-memory T cell phenotype, and produced inflammatory cytokines. Moreover, exFoxp3 cell numbers increased in inflamed tissues under autoimmune conditions. Adoptive transfer of autoreactive exFoxp3 cells led to the rapid-onset of diabetes. Finally, T cell receptor repertoire analyses suggested that exFoxp3 cells develop from both natural and adaptive Treg cells. Thus, the generation of potentially autoreactive effector T cells as a consequence of Foxp3 instability has important implications for understanding autoimmune disease pathogenesis.

Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation

“…Further studies suggested that in mice, Foxp3 þ T cells also can lose Foxp3 expression and convert into Th17 cells or pathogenic ''exFoxp3'' cells. 51,52 With regard to these findings, it was therefore unclear whether those Foxp3 þ RORgt þ T cells that can be found in lymphoid organs and intestinal LP of mice represent a stable Treg subpopulation or just an intermediate stage during Treg or Th17 cell development. To answer this question, we generated Foxp3 RFP RORgt GFP double reporter mice that enabled us to perform a comprehensive phenotypical and functional analysis of the Foxp3 þ RORgt þ T-cell population and to study their lineage stability.…”

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

“…Therefore, the stable expression of Foxp3 is critical, and it is still contentious whether Foxp3 instability is pathologically relevant (17)(18)(19)(20)(21). Stable expression of Foxp3 is accompanied by epigenetic modulation of the CpG-rich conserved noncoding sequence 2 (CNS2) within the first intron of the Foxp3 locus (22)(23)(24)(25).…”

Human FOXP3 and cancer

“…Furthermore, adoptive transfer of Treg cells into lymphopenic hosts also leads to a loss of Foxp3 expression and their differentiation into so-called follicular T-helper cells (Tsuji et al, 2009). Following FOXP3 downregulation, Treg can even exert effector cell activities including the production of IL-17 or IFNg (Zhou et al, 2009). This illustrates that stability of foxp3 expression is directly affecting the plasticity of Treg.…”