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 |
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Hauptverfasser: | , , , , |
Format: | Artikel |
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. |
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ISSN: | 1529-2908 1529-2916 |
DOI: | 10.1038/ni.2499 |