IL-6 Inhibits Upregulation of Membrane-Bound TGF-β 1 on CD4+ T Cells and Blocking IL-6 Enhances Oral Tolerance
| Autor: | Howard L. Weiner, Rafael M. Rezende, Andre Pires da Cunha, Chantal Kuhn, Hanane M’Hamdi |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
CD4-Positive T-Lymphocytes
STAT3 Transcription Factor 0301 basic medicine CD3 Complex Ovalbumin Immunology Biology Article Immune tolerance Proinflammatory cytokine Transforming Growth Factor beta1 Mice 03 medical and health sciences Interleukin 21 0302 clinical medicine Downregulation and upregulation Immune Tolerance Animals Immunology and Allergy Secretion Interleukin-6 Antibodies Monoclonal Membrane Proteins FOXP3 Molecular biology In vitro Up-Regulation Mice Inbred C57BL 030104 developmental biology biology.protein Interleukin-2 Antibody 030215 immunology |
| Zdroj: | The Journal of Immunology. 198:1202-1209 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Oral administration of Ag induces regulatory T cells that express latent membrane-bound TGF-β (latency-associated peptide [LAP]) and have been shown to play an important role in the induction of oral tolerance. We developed an in vitro model to study modulation of LAP+ on CD4+ T cells. The combination of anti-CD3 mAb, anti-CD28 mAb, and recombinant IL-2 induced expression of LAP on naive CD4+ T cells, independent of Foxp3 or exogenous TGF-β. In vitro generated CD4+LAP+Foxp3− T cells were suppressive in vitro, inhibiting proliferation of naive CD4+ T cells and IL-17A secretion by Th17 cells. Assessing the impact of different cytokines and neutralizing Abs against cytokines, we found that LAP induction was decreased in the presence of IL-6 and IL-21, and to a lesser extent by IL-4 and TNF-α. IL-6 abrogated the in vitro induction of CD4+LAP+ T cells by STAT3-dependent inhibition of Lrrc32 (glycoprotein A repetitions predominant [GARP]), the adapter protein that tethers TGF-β to the membrane. Oral tolerance induction was enhanced in mice lacking expression of IL-6R by CD4+ T cells and by treatment of wild-type mice with neutralizing anti-IL-6 mAb. These results suggest that proinflammatory cytokines interfere with oral tolerance induction and that blocking the IL-6 pathway is a potential strategy for enhancing oral tolerance in the setting of autoimmune and inflammatory diseases. |
| Databáze: | OpenAIRE |
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