Cell-Autonomous Constitutive gp130 Signaling in T Cells Amplifies T_H17 Cell Responses and Causes Severe Lung Inflammation

IL-6 plays a fundamental role in T cell differentiation and is strictly controlled by surface expression and shedding of IL-6R. IL-6 also acts on other cells that might affect T cell maturation. To study the impact of cell-autonomous and uncontrolled IL-6 signaling in T cells, we generated mice with a constitutively active IL-6R gp130 chain (Lgp130) expressed either in all T cells (Lgp130 3 CD4Cre mice) or inducible in CD4(+) T cells (Lgp130 3 CD4CreER(T2) mice). Lgp130 3 CD4Cre mice accumulated activated T cells, including T(H)17 cells, in the lung, resulting in severe inflammation. Tamoxifen treatment of Lgp130 3 CD4CreER(T2) mice caused Lgp130 expression in 40-50% of CD4(+) T cells, but mice developed lung disease only after several months. Lgp130(+) CD4(+) T cells were also enriched for T(H)17 cells; however, there was concomitant expansion of Lgp1302 regulatory T cells, which likely restricted pathologic Lgp130+ T cells. In vitro, constitutive gp130 signaling in T cells enhanced but was not sufficient for T(H)17 cell differentiation. Augmented T(H)17 cell development of Lgp130(+) T cells was also observed in Lgp130 3 CD4CreER(T2) mice infected with Staphylococcus aureus, but gp130 activation did not interfere with formation of T(H)1 cells against Listeria monocytogenes. Lgp130(+) CD4(+) T cells acquired a memory T cell phenotype and persisted in high numbers as a polyclonal T cell population in lymphoid and peripheral tissues, but we did not observe T cell lymphoma formation. In conclusion, cell-autonomous gp130 signaling alters T cell differentiation. Although gp130 signaling is not sufficient for T(H)17 cell differentiation, it still promotes accumulation of activated T cells in the lung that cause tissue inflammation.