Selective ablation of thymic and peripheral Foxp3+ regulatory T cell development

Abstract

Foxp3+ Treg cells of thymic (tTreg) and peripheral (pTreg) developmental origin are thought to synergistically act to ensure immune homeostasis, with self-reactive tTreg cells primarily constraining autoimmune responses. We exploited tTreg-specific GFP/Cre recombinase activity to selectively ablate either tTreg ({Delta}tTreg) or pTreg ({Delta}pTreg) cell development. In contrast to the tTreg cell behavior in {Delta}pTreg mice, pTreg cells with a highly activated suppressor phenotype replenished the Treg cell pool of C57BL/6.{Delta}tTreg mice, preventing early mortality and fatal autoimmunity. Even with advancing age, pTreg cells largely maintained immune tolerance in C57BL/6.{Delta}tTreg mice. However, only two generations of (C57BL/6>NOD) backcrossing precipitated severe disease lethality associated with a distinct, partially overlapping pattern of organ-specific autoimmunity. Genetic association studies defined a small set of autoimmune risk loci sufficient to unleash a particularly severe form of diabetes, including genes known to impinge on Treg cell biology. Thus, pTreg cells exhibit an unexpectedly high functional adaptability, emphasizing their importance as mediators of bystander effects to ensure self-tolerance. SUMMARYThis study in complementary loss-of-function mouse models uncovers an unexpected functional plasticity of pTreg cells in constraining systemic autoimmune responses in the absence of tTreg cells and identifies tTreg cells as primary regulators of {beta}-cell autoimmunity in type 1 diabetes.