The IL-6R α chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo
Aysefa Doganci, … , Peter R. Galle, Susetta Finotto
Aysefa Doganci, … , Peter R. Galle, Susetta Finotto
Published February 1, 2005
Citation Information: J Clin Invest. 2005;115(2):313-325. https://doi.org/10.1172/JCI22433.
View: Text | PDF | Corrigendum
Categories: Article Immunology

The IL-6R α chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo

Abstract

The cytokine IL-6 acts via a specific receptor complex that consists of the membrane-bound IL-6 receptor (mIL-6R) or the soluble IL-6 receptor (sIL-6R) and glycoprotein 130 (gp130). In this study, we investigated the role of IL-6R components in asthma. We observed increased levels of sIL-6R in the airways of patients with allergic asthma as compared to those in controls. In addition, local blockade of the sIL-6R in a murine model of late-phase asthma after OVA sensitization by gp130–fraction constant led to suppression of Th2 cells in the lung. By contrast, blockade of mIL-6R induced local expansion of Foxp3-positive CD4+CD25+ Tregs with increased immunosuppressive capacities. CD4+CD25+ but not CD4+CD25– lung T cells selectively expressed the IL-6R α chain and showed IL-6–dependent STAT-3 phosphorylation. Finally, in an in vivo transfer model of asthma in immunodeficient Rag1 mice, CD4+CD25+ T cells isolated from anti–IL-6R antibody–treated mice exhibited marked immunosuppressive and antiinflammatory functions. IL-6 signaling therefore controls the balance between effector cells and Tregs in the lung by means of different receptor components. Furthermore, inhibition of IL-6 signaling emerges as a novel molecular approach for the treatment of allergic asthma.

Authors

Aysefa Doganci, Tatjana Eigenbrod, Norbert Krug, George T. De Sanctis, Michael Hausding, Veit J. Erpenbeck, El-Bdaoui Haddad, Edgar Schmitt, Tobias Bopp, Karl-J. Kallen, Udo Herz, Steffen Schmitt, Cornelia Luft, Olaf Hecht, Jens M. Hohlfeld, Hiroaki Ito, Norihiro Nishimoto, Kazuyuki Yoshizaki, Tadamitsu Kishimoto, Stefan Rose-John, Harald Renz, Markus F. Neurath, Peter R. Galle, Susetta Finotto

×

Figure 8

Options: View larger image (or click on image) Download as PowerPoint
CD4+CD25+ T cells from OVA-sensitized mice can inhibit CD4+CD25– T cell–...
CD4+CD25+ T cells from OVA-sensitized mice can inhibit CD4+CD25– T cell–induced experimental asthma in Rag1–/– mice. (A–F) Cotransfer of CD4+CD25+ and CD4+CD25– spleen T cells into Rag1–/– mice. CD4+CD25+ and CD4+CD25– T cells were isolated from the spleens of OVA-sensitized and -challenged mice given IgG-control antibodies or anti–IL-6R antibodies. CFSE-labeled CD4+CD25– spleen T cells from OVA-sensitized mice (5 × 105; CSFE-labeled indicated with asterisks) were cotransferred i.p. with either 5 × 105 unlabeled CD4+CD25– T cells (A and D) or CD4+CD25+ T cells (B, C, E, and F) into immunocompromised Rag1 knockout mice. Cotransfer of CD4+CD25+ T cells from anti–IL-6R–treated (C and F) or IgG-treated (B and E) mice suppressed allergic airway inflammation induced by transfer of CD4+CD25– T cells from OVA-sensitized mice. Magnification, ×100 (A–C), ×400 (D–F). Mice receiving only CD4+CD25– T cells showed CFSE-positive cells in the lung (H), whereas mice receiving CD4+CD25+ T cells as well showed a marked decrease in the number of CFSE-positive cells (G and I), suggesting a CD4+CD25+ T cell–mediated suppression of effector CD4+CD25– T cell proliferation. Results in G were obtained by calculating the average number of CFSE-positive cells per high power field (HPF) (n = 30). ***P = 0.001.