| CD4+ regulatory T cells expressing the transcription factor Foxp3 are critical for maintaining immune homeostasis. Regulatory T cells that mature from thymic precursors (nTreg) prevent autoimmunity to self-antigen while those maturing from naïve CD4+ T cells in the periphery (iTreg) are critical in preventing mucosal injury and promoting tolerance to alloantigen. Previous findings have linked the signals transmitted through T cell-expressed C3a receptor (C3aR) and C5a receptor (C5aR) to the activation and expansion of effector T cells. This raised the possibility that C3aR/C5aR signaling on Treg could impact the induced strength of T cell immune responses. Herein we demonstrate that signaling through C3aR and C5aR diminishes nTreg function and negatively affects the generation and stability of iTreg. Genetic and pharmacological blockade of C3aR/C5aR signal transduction in nTreg augments suppression, abrogates autoimmune colitis and prolongs allogeneic skin graft survival. The absence of C3aR/C5aR signaling on naïve CD4+ T cells enhances generation of alloreactive iTreg, augments in vivo iT reg stability, and improves iTreg-mediated protection against immunity in models of graft versus host disease (GVHD). In both nTreg and iTreg, mechanisms involve C3a/C5a-induced phosphorylation of AKT and as a consequence, phosphorylation and cytoplasmic sequestration of the transcription factor Foxo1. C3a and C5a stimulation also reduced Foxp3 expression in nTreg and antagonized Foxp3 expression among iT reg. The finding that C3a/C3aR and C5a/C5aR modulate Treg function suggests targeting of this pathway could be exploited to manipulate pathogenic or protective T cell responses. |
