Research Fellow BCH, Harvard Med. School Boston, Massachusetts, United States
Disclosure(s):
Mohammad Adeel Zafar, PhD: No financial relationships to disclose
Introduction/Rationale: 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 (∆Treg) in periphery. ∆Tregs 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, ∆Tregs that acquire Teff transcriptome promote autoimmunity, are characterized by loss of CD25 and Foxp1 expression and impaired suppressive activity. Further, depletion of ∆Tregs 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 ∆Tregs 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/IL2, CDK8/19 inhibitor and STAT5b gain of function prevent the degeneration of ∆Treg cells in vivo resulting in increased frequency of CD25+ ∆Tregs and improvement in the scurfy phenotype, supporting the role of IL2 signaling in maintaining Treg cell attributes of ∆Treg cells in absence of Foxp3 expression. ∆Treg-specific Foxp1 deletion led to a steep decrease in the frequency of ∆Treg, lower CD25 expression, increased T-bet expression, and a reduction in the Foxp3 locus activity, suggesting that Foxp1 loss accelerate the degeneration process of ∆Treg cells.
Conclusion: Our results indicate that IL2 signaling is sufficient to maintain ∆Treg regulatory capacity, while Foxp1 expression is necessary to stabilize their identity and prevent terminal degeneration.
