Absent C3a and C5a receptor signaling into CD4(+) T cells enables auto-inductive TGF-β1 signaling and induction of Foxp3(+) T regulatory cells

C3a and C5a receptor (C3aR and C5aR) signaling by dendritic cells and CD4(+) cells provides costimulatory and survival signals to T effector cells. Here, we demonstrate that when C3aR and C5aR signals are not transduced into CD4(+) cells, PI-3Kγ-AKT-mTOR signaling ceases, PKA activation increases, auto-inductive transforming growth factor- β1 (TGF-β1) signaling initiates, and CD4(+) cells become Foxp3(+) T regulatory cells (iT(regs)). Endogenous TGF-β1 suppresses C3aR and C5aR signaling by preventing C3a and C5a production and upregulating C5L2, an alternate C5a receptor. Absent C3aR and C5aR signaling decreases costimulatory molecule and interleukin-6 production and augments interleukin-10 production. The resulting iT(regs) exert robust suppression, possess enhanced stability, and suppress ongoing autoimmune disease. Human iT(regs) with potent suppressor activity can be induced exploiting this insight.