Cell-Autonomous Constitutive gp130 Signaling in T Cells Amplifies TH17 Cell Responses and Causes Severe Lung Inflammation

TY - JOUR

T1 - Cell-Autonomous Constitutive gp130 Signaling in T Cells Amplifies TH17 Cell Responses and Causes Severe Lung Inflammation

AU - Heinig, Lisa Charlotte

AU - Huth, Emily Valentina Madelaine

AU - Yan, Karsten

AU - Schumacher, Neele

AU - Nawrocki, Mikolaj

AU - Lory, Niels Christian

AU - Bradtke, Peter

AU - Bertram, Tabea

AU - Rattay, Guido

AU - Schmid, Joanna

AU - Huber, Samuel

AU - Wiech, Thorsten

AU - Biosciences and Medical Biology, Paris Lodron University Salzburg, Salzburg, Austria, Department

AU - Rose-John, Stefan

AU - Mittrücker, Hans-Willi

N1 - Copyright © 2023 by The American Association of Immunologists, Inc.

PY - 2023/6/1

Y1 - 2023/6/1

N2 - 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 × CD4Cre mice) or inducible in CD4+ T cells (Lgp130 × CD4CreERT2 mice). Lgp130 × CD4Cre mice accumulated activated T cells, including TH17 cells, in the lung, resulting in severe inflammation. Tamoxifen treatment of Lgp130 × CD4CreERT2 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 TH17 cells; however, there was concomitant expansion of Lgp130- regulatory T cells, which likely restricted pathologic Lgp130+ T cells. In vitro, constitutive gp130 signaling in T cells enhanced but was not sufficient for TH17 cell differentiation. Augmented TH17 cell development of Lgp130+ T cells was also observed in Lgp130 × CD4CreERT2 mice infected with Staphylococcus aureus, but gp130 activation did not interfere with formation of TH1 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 TH17 cell differentiation, it still promotes accumulation of activated T cells in the lung that cause tissue inflammation.

AB - 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 × CD4Cre mice) or inducible in CD4+ T cells (Lgp130 × CD4CreERT2 mice). Lgp130 × CD4Cre mice accumulated activated T cells, including TH17 cells, in the lung, resulting in severe inflammation. Tamoxifen treatment of Lgp130 × CD4CreERT2 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 TH17 cells; however, there was concomitant expansion of Lgp130- regulatory T cells, which likely restricted pathologic Lgp130+ T cells. In vitro, constitutive gp130 signaling in T cells enhanced but was not sufficient for TH17 cell differentiation. Augmented TH17 cell development of Lgp130+ T cells was also observed in Lgp130 × CD4CreERT2 mice infected with Staphylococcus aureus, but gp130 activation did not interfere with formation of TH1 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 TH17 cell differentiation, it still promotes accumulation of activated T cells in the lung that cause tissue inflammation.

KW - Animals

KW - Mice

KW - Cell Differentiation

KW - Cytokine Receptor gp130/metabolism

KW - Inflammation

KW - Interleukin-6/metabolism

KW - Lung/metabolism

KW - Pneumonia

KW - Th1 Cells/metabolism

KW - Th17 Cells/metabolism

U2 - 10.4049/jimmunol.2200461

DO - 10.4049/jimmunol.2200461

M3 - SCORING: Journal article

C2 - 37058116

VL - 210

SP - 1717

EP - 1727

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 11

ER -