title: IL-6 Inhibits Upregulation of Membrane-Bound TGF-β 1 on CD4+ T Cells and Blocking IL-6 Enhances Oral Tolerance.
abstract: 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.
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Chantal
authors.initials: C
authors.lastname: Kuhn
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Rafael Machado
authors.identifier: 0000-0003-3998-8012
authors.initials: RM
authors.lastname: Rezende
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Hanane
authors.initials: H
authors.lastname: M'Hamdi
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Andre Pires
authors.initials: AP
authors.lastname: da Cunha
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 hweiner@rics.bwh.harvard.edu.
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*; D015854:Up-Regulation; D000093242:Interleukin-6 Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007376:Interleukin-2; D015850:Interleukin-6; D008565:Membrane Proteins; D010047:Ovalbumin; D050796:STAT3 Transcription Factor; D053773:Transforming Growth Factor beta1; D000093242:Interleukin-6 Inhibitors; C087215:LRRC32 protein, human; C494087:Stat3 protein, mouse