Mechanisms of pTreg development from anergic precursors

 

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B736
Abstract ID: 4896

Presenting Author:
Svetlana Ristin , Graduate Student at Univ. of Miami Miller Sch. of Med.

Abstract:

Regulatory T cells (Tregs) are generated either in the thymus or periphery. While factors governing ‘natural’ thymus-derived Treg (nTreg) development are well described, there is limited understanding of those directing peripheral regulatory T cell (pTreg) differentiation. Using a mouse model of oral tolerance, we demonstrate that T cells must first enter a state of anergy prior to becoming pTreg, suggesting a two-stage process. Stage 1 is characterized by T cell anergy with prominent induction of ‘checkpoint’ inhibitory receptors, most notably PD-1 and CD200. Stage 2 then follows with pTreg conversion or, alternatively, adoption of a ‘deep’ anergic state. Given this induction of inhibitory receptors, we assessed the impact of PD-1 deficiency and found that T cells proliferate more and convert less to pTreg. Intriguingly, we also find that PD-1 expression distinguishes pTreg derived from anergic precursors from those derived from non-anergic precursors. Based on scRNAseq data showing that IL-2-STAT5 signaling is highly active in pTreg, we also assessed the role of IL-2Ra and STAT5 and found that both are strictly required for induction of pTreg, suggesting that this pathway drives transition from Stage 1 to Stage 2 tolerance. Taken together, our data shows that transition from Treg-independent (Stage 1) to Treg-dependent (Stage 2) tolerance is driven by cell extrinsic signals provided by inhibitory receptors and IL-2-STAT5 signaling which combine to induce pTreg development.