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

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  • Additional Information
    • Source:
      Publisher: American Association of Immunologists Country of Publication: United States NLM ID: 2985117R Publication Model: Print Cited Medium: Internet ISSN: 1550-6606 (Electronic) Linking ISSN: 00221767 NLM ISO Abbreviation: J Immunol Subsets: MEDLINE
    • Publication Information:
      Publication: Bethesda, MD : American Association of Immunologists
      Original Publication: Baltimore : Williams & Wilkins, c1950-
    • Subject Terms:
      Pneumonia* ; Th17 Cells*/metabolism; Animals ; Mice ; Cell Differentiation ; Cytokine Receptor gp130/metabolism ; Inflammation ; Interleukin-6/metabolism ; Lung/metabolism ; Th1 Cells/metabolism
    • Abstract:
      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.
      (Copyright © 2023 by The American Association of Immunologists, Inc.)
    • Accession Number:
      133483-10-0 (Cytokine Receptor gp130)
      0 (Interleukin-6)
      0 (Il6st protein, mouse)
    • Publication Date:
      Date Created: 20230414 Date Completed: 20230517 Latest Revision: 20230621
    • Publication Date:
      20230622
    • Accession Number:
      10.4049/jimmunol.2200461
    • Accession Number:
      37058116