Soluble GARP has potent antiinflammatory and immunomodulatory impact on human CD4+ T cells
| Autor: | Heiko Stahl, Susanne A. Hahn, Franz-Joseph Schneider, Christian Becker, Helmut Jonuleit, Andrea Tuettenberg, Anita Correll |
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| Rok vydání: | 2013 |
| Předmět: |
CD4-Positive T-Lymphocytes
Cellular differentiation Blotting Western Transplantation Heterologous Immunology Anti-Inflammatory Agents Graft vs Host Disease Apoptosis Biology Real-Time Polymerase Chain Reaction T-Lymphocytes Regulatory Biochemistry Proinflammatory cytokine Interferon-gamma Mice Transforming Growth Factor beta medicine Animals Humans RNA Messenger Cells Cultured Cell Proliferation Inflammation Mice Knockout Reverse Transcriptase Polymerase Chain Reaction Effector Interleukins Membrane Proteins Interleukin Peripheral tolerance FOXP3 Cell Differentiation Forkhead Transcription Factors Cell Biology Hematology Flow Cytometry medicine.disease Cell biology Transplant rejection DNA-Binding Proteins Animals Newborn Humanized mouse Interleukin-2 Female Signal Transduction |
| Zdroj: | Blood. 122:1182-1191 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Glycoprotein A repetitions predominant (GARP) is expressed on the surface of activated human regulatory T cells (Treg) and regulates the bioavailability of transforming growth factor-β (TGF-β). GARP has been assumed to require membrane anchoring. To investigate the function of GARP in more detail, we generated a soluble GARP protein (sGARP) and analyzed its impact on differentiation and activation of human CD4⁺ T cells. We demonstrate that sGARP efficiently represses proliferation and differentiation of naïve CD4⁺ T cells into T effector cells. Exposure to sGARP induces Foxp3, decreases proliferation and represses interleukin (IL)-2 and interferon-γ production, resulting in differentiation of naïve T cells into induced Treg. This is associated with Smad2/3 phosphorylation and partially inhibited by blockade of TGF-β signaling. Furthermore, in the presence of the proinflammatory cytokines IL-6 and IL-23, sGARP facilitates the differentiation of naïve T cells into Th17 cells. More important, in a preclinical humanized mouse model of xenogeneic graft-versus-host disease (GVHD), sGARP prevents T cell-mediated destructive inflammation by enhancing Treg and inhibiting T effector cell activity. These results demonstrate a crucial role of sGARP in modulation of peripheral tolerance and T effector cell function, opening the possibility to use sGARP as a potent immunomodulator of inflammatory diseases including transplant rejection, autoimmunity, and allergy. |
| Databáze: | OpenAIRE |
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