IL2R signaling and Foxp1 expression maintain Treg cell identity in the absence of Foxp3

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B745
Abstract ID: 4263

Presenting Author:
Louis-Marie Charbonnier , Assistant Professor at Boston Children's Hosp., Harvard Med. Sch.

Abstract:

Upon Foxp3 loss-of-function, Treg development gives rise to a heterogeneous population of Tregs (∆Tregs). ∆Tregs retain the core Treg transcriptome and epigenetic imprint and can be classified based on the expression of CD25, and Foxp3 locus activity. We propose a stepwise degeneration driven by a decrease in IL2R signaling and subsequent loss of Foxp1 expression.

CD25⁺∆Treg gene expression profile, as compared to the one of CD25^–∆Tregs, presented increased Treg transcriptomic signature. CD25^-∆Tregs were biased toward Th1, presented impaired suppressive capacity,Foxp3 locus activity and Foxp1 expression. Treatment with IL2/anti-IL2 complex ameliorated the disease severity and survival of Foxp3-deficient mice. Additionally, ∆Treg-specific STAT5 gain of function decreased their Th1-bias, while promoting their suppressive function, supporting the role of IL2 signaling in maintaining Treg identity of CD25⁺∆Tregs. ∆Treg-specific Foxp1 deletion led to a steep decrease in ∆Treg frequency and Foxp3 locus activity while increased Th1-bias, suggesting that Foxp1 loss drives ∆Treg degeneration. Moreover, the beneficial effect of treatment with IL2/anti-IL2 complex requires ∆Treg Foxp1 expression. 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.