Sustained gp130 signaling in T cells causes unrestricted TH17 cell responses, severe lung inflammation and increased bone porosity
HUTH E. 1, BRADTKE P. 1, RATTAY G. 1, BRYLKA L. 1, WIECH T. 1, ROSE-JOHN S. 2, YORGAN T. 1, MITTRÜCKER H. 1
1 University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2 Christian-Albrechts-University, Kiel, Germany
IL-6 plays an important role in T cell differentiation and acts on a wide spectrum of cells that also affect T-cell maturation. After binding of IL-6 to the IL-6Rα, the IL-6/IL-6R complex activates the signaling receptor subunit gp130. To study the impact IL-6 signaling on T cells, we generated mice with a constitutively active gp130 expressed on all conventional T cells (Lgp130×CD4Cre mice). Lgp130×CD4Cre mice developed severe lung inflammation that resulted in a reduced life span of approx. 100 days. Lungs of mice showed thickened alveolar walls and pronounced mononuclear cell infiltration. Lung inflammation was also associated with massive accumulation of activated T cells, particularly of TH17 cells, and decreased numbers of regulatory T cells (Treg cells). In vitro cultivation of Lgp130+ T cells revealed that Lgp130 signaling alone was not sufficient for induction of CD4+ and CD8+ T cell differentiation and for T cell survival but required T cell activation through the TCR. In addition to the lung inflammation, Lgp130×CD4Cre mice displayed pronounced changes in bone morphology with increased cortical and trabecular bone porosity of the femur and tibia, and decreased numbers and disturbed balance of osteoclasts and osteoblasts. In conclusion, these results suggest that unrestricted gp130 signaling promotes TH17 cell differentiation and represses Treg cell responses with lung inflammation and changes in bone morphology as severe consequences.