Stepwise progression from tolerogenic precursors to anergic and regulatory CD4 T cells 2838

Abstract Description Molecular mechanisms underlying T cell anergy and its relationship with other tolerogenic states remains unclear. Using a mouse model of oral tolerance, we demonstrate that CD4 T cell anergy and peripheral regulatory T cells (pTreg) are sequentially engaged, suggesting a two-stage process. First, T cells enter a multipotent ‘proto-anergic’ state, characterized by prominent induction of checkpoint inhibitory receptors, most notably PD-1, and bearing elements of both classical anergy and T follicular helper cells (Tfh) responses (Stage 1). Then, they proceed to terminal tolerogenic states, becoming either terminally anergic or pTreg (Stage 2). Given the induction of inhibitory receptors, we assessed the impact of PD-1 deficiency and found that tolerance is broken; T cells proceed to effector differentiation and fail to become pTreg, suggesting a key role for PD-1 in oral tolerance and maintenance of the ‘proto-anergic’ state. Based on scRNAseq data indicating that IL-2-STAT5 signaling is highly active in T cells responding to ingested antigen, we also assessed the role of IL-2Ra and STAT5 and found that both are strictly required for pTreg induction, suggesting this pathway drives transition from Stage 1 to Stage 2 tolerance. Taken together, these data establish that transition from Stage 1 to Stage 2 tolerance is driven by inhibitory receptors and IL-2-STAT5 signaling which induce pTreg development, prevent deleterious T effector responses and, in turn, mediate oral tolerance. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)