IL2 signaling and Foxp1 expression maintain Treg identity in the absence of Foxp3

Abstract Regulatory T cells (Treg) have a pivotal role in tolerance and immune homeostasis. In autoimmunity, Treg are destabilized degenerate, loosing Foxp3 expression compromising their regulatory function, while gaining effector cell (Teff)-like phenotype. Upon loss-of-function, development gives rise to heterogeneous population of (ΔTreg). ΔTreg retain the core transcriptome epigenetic imprint can be classified based on high-affinity IL-2 receptor-alpha, CD25, locus activity. We herein propose stepwise degeneration driven by decrease IL2/CD25 signaling subsequent loss Foxp1 expression. CD25 +ΔTreg profile, as compared one −ΔTreg cells, presented increased levels genes typically expressed Treg, such Il2ra Il10. Consistently, were biased toward Th1, impaired suppressive capacity, downregulated Foxp1. Treatment with IL2/aIL2 STAT5b gain function upregulated decreased Th1 bias inflammation, supporting IL2 halting passage from +to −ΔTreg. ΔTreg-specific depletion led steep frequency ΔTreg, T-bet expression, reduction activity, suggesting that drives ΔCD25 −ΔTregs into terminally degenerated state. Our results indicate is sufficient maintain necessary stabilize identity prevent terminal degeneration. currently doing scRNAseq ChIPseq elucidate molecular mechanisms which absence Foxp3. National Institutes Health grant R01AI153174