IL2 signaling and Foxp1 expression maintain Treg identity in the absence of Foxp3 2260415

Abstract

Abstract Introduction Regulatory T cells (Treg) have a pivotal role in tolerance and immune homeostasis. In autoimmunity, Treg are destabilized and degenerate into exTregs, loosing Foxp3 expression and compromising their regulatory function, while gaining a T effector cell (Teff)-like phenotype. Methods By utilizing a Foxp3 loss-of-function mutation model, we show that Treg development gives rise to a heterogeneous population of Treg cells (ΔTreg) in periphery. ΔTregs that retain the core Treg transcriptome and epigenetic imprint have residual suppressive activity and can be classified based on the expression of CD25. On the other hand, ΔTregs that acquire Teff transcriptome promote autoimmunity, are characterized by loss of CD25 and Foxp1 expression and impaired suppressive activity. Further, depletion of ΔTregs in DSS induced colitis model reduced the severity of disease confirming the teff like function of these cells. We herein propose a stepwise degeneration of ΔTregs from CD25+ Treg like population to CD25— Teff like population and finally exTregs with a loss of Foxp3 locus activity, driven by reduced IL2/CD25 signaling and Foxp1 expression while acquiring Teff programs. Results Treatment with IL2/αIL2, CDK8/19 inhibitor and STAT5b gain of function prevent the degeneration of ΔTreg cells in vivo resulting in increased frequency of CD25+ ΔTregs and improvement in the scurfy phenotype, supporting the role of IL2 signaling in maintaining Treg cell attributes of ΔTreg cells in absence of Foxp3 expression. ΔTreg-specific Foxp1 deletion led to a steep decrease in the frequency of ΔTreg, lower CD25 expression, increased T-bet expression, and a reduction in the Foxp3 locus activity, suggesting that Foxp1 loss accelerate the degeneration process of ΔTreg cells. Conclusion Our results indicate that IL2 signaling is sufficient to maintain ΔTreg regulatory capacity, while Foxp1 expression is necessary to stabilize their identity and prevent terminal degeneration. Funding Source NIH NIAD Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)