Absent C3a and C5a receptor signaling into CD4+ T cells enables auto-inductive TGF-β1 signaling and induction of Foxp3+ T regulatory cells
| Autor: | Feng Lin, Michael G. Strainic, Fengqi An, M. Edward Medof, Ethan M. Shevach |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Immunology
Complement C5a Mice Transgenic chemical and pharmacologic phenomena Cell Communication Biology Jurkat cells T-Lymphocytes Regulatory Article Transforming Growth Factor beta1 03 medical and health sciences Mice 0302 clinical medicine Immunology and Allergy Cytotoxic T cell Animals Class Ib Phosphatidylinositol 3-Kinase IL-2 receptor Antigen-presenting cell Receptor Anaphylatoxin C5a 030304 developmental biology Interleukin 3 0303 health sciences Interleukin-6 ZAP70 TOR Serine-Threonine Kinases FOXP3 Cell Differentiation Forkhead Transcription Factors Receptor Cross-Talk Natural killer T cell Cyclic AMP-Dependent Protein Kinases Cell biology Interleukin-10 Receptors Complement Gene Expression Regulation Complement C3a Receptors Chemokine Proto-Oncogene Proteins c-akt 030215 immunology Signal Transduction |
| Zdroj: | Nature immunology |
| ISSN: | 1529-2916 1529-2908 |
| Popis: | Signaling through the G protein-coupled receptors for the complement fragments C3a and C5a (C3aR and C5aR, respectively) by dendritic cells and CD4(+) cells provides costimulatory and survival signals to effector T cells. Here we found that when signals from C3aR and C5aR were not transduced into CD4(+) cells, signaling via the kinases PI(3)Kγ, Akt and mTOR ceased, activation of the kinase PKA increased, autoinductive signaling by transforming growth factor-β1 (TGF-β1) initiated and CD4(+) T cells became Foxp3(+) induced regulatory T cells (iT(reg) cells). Endogenous TGF-β1 suppressed signaling through C3aR and C5aR by preventing the production of C3a and C5a and upregulating C5L2, an alternative receptor for C5a. The absence of signaling via C3aR and C5aR resulted in lower expression of costimulatory molecules and interleukin 6 (IL-6) and more production of IL-10. The resulting iT(reg) cells exerted robust suppression, had enhanced stability and suppressed ongoing autoimmune disease. Antagonism of C3aR and C5aR can also induce functional human iT(reg) cells. |
| Databáze: | OpenAIRE |
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