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, aut...

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Veröffentlicht in:Nature immunology 2012-12, Vol.14 (2), p.162-171
Hauptverfasser: Strainic, Michael G., Shevach, Ethan M., An, Fengqi, Lin, Feng, Medof, M. Edward
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Sprache:eng
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Zusammenfassung: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.
ISSN:1529-2908
1529-2916
DOI:10.1038/ni.2499