Abstract
Extrathymic T cell tolerance is an active, highly regulated process by which the adaptive immune system learns to manage MHC restricted self or harmless environmental antigens. T cell tolerance towards innocuous antigens is mediated by 3 complementary mechanisms: deletion, T cell anergy and peripheral regulatory T cells (pTreg) induction, that work together to suppress effector T cell responses that could otherwise lead to harmful allergic reactions. However, molecular mechanisms underlying T cell anergy and its relationship with pTreg remain unclear.
Using mouse models, we traced the evolution of tolerogenic CD4+ "helper" T cell responses during antigen feeding at steady state and in the context of inflammation. Following on the bedrock finding that anergy and pTreg are sequential, we propose a two-stage paradigm whereby T cells first pass through a multipotent "proto-anergic" state, then proceed to terminal states subsequently becoming either terminally anergic or pTreg. Stage 1 is characterized by transient induction of BCL6 and PD1 which impose T follicular helper (Tfh) and stem-like features while instigating both anergy and pTreg differentiation. Stage 2 is characterized by IL-2-STAT5 signaling, which drives pTreg expansion, or by diminution of antigen responsiveness, leading to cell death. Importantly, this two-stage paradigm reconciles traditional views of anergy with emergent ideas on multipotency and stemness by introducing three concepts: (1) progressive anergy, the idea that anergy deepens over time, (2) proto-anergic progenitors, a multipotent anergic state that begets both tolerogenic and effector fates, and (3) terminal anergy, a unipotent anergic state that culminates in death-by-neglect.