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Research Article: Second-order regulation: IFN-? suppresses IL-17A-mediated type 3 inflammation

Date Published: 2026-05-11

Abstract:
T helper 1 (T H 1) cells often accompany T H 17 cells across diverse tissues in health and disease, including the lungs. However, roles for the T H 1 effector cytokine, IFN-?, in T H 17-driven type 3 inflammation is unclear. We devised a simplified reductionistic model to determine the role of IFN-? in IL-17A-driven inflammation during Streptococcus pneumoniae ( Spn ) infection in vivo. Briefly, intratracheal instillation of Spn along with recombinant TNF-? and IL-17A was used to mimic rapid Spn -specific, T H 17-driven, type 3 inflammation seen in lungs on memory recall infection with Spn . Co-instillation of recombinant IFN-? was used to probe the role for this T H 1 cell-derived effector cytokine in anti- Spn immune response. Immune cellularity in bronchoalveolar lavage (BAL) was used to determine impacts of IFN-? on type 3 inflammation in murine airways. Mice sufficient for- or lacking- IFN-? or STAT1 were used to assess the immunoregulatory functions of IFN-? in vivo. IFN-? promptly muted IL-17A-induced inflammatory cell accumulation in Spn -infected airways through a STAT1-dependent mechanism. Both female and male mice demonstrated similar anti-inflammatory effects of IFN-? on type 3 inflammation. We find that the impact of IFN-? was dependent on the degree of type 3 inflammation such that IFN-?’s immunoregulatory role became more striking at lower concentrations of all the three cytokines. Of note, the immunoregulatory effect of IFN-? against T H 17-driven type 3 inflammation was also evident in physiologically relevant settings: while immunized wild type (WT) mice controlled lethal Spn infection, immunized IFN-? knockout mice exhibited even better Spn clearance. This improved antimicrobial resistance, however, was accompanied by heightened airway neutrophilia (which could be phenocopied by mere neutralization of IFN-? in immunized wild type mice) suggesting risk for immunopathology. Our findings identify a distinct immunoregulatory mechanism that operates within non-lymphoid tissues, where IFN-? limits IL-17A-mediated type 3 inflammation via STAT1. Thus, the frequent accompaniment of T H 17 cells with T H 1 cells may represent a conserved mechanism that restrains immunopathological potential of T H 17-driven neutrophilic inflammation via STAT1 signaling in non-lymphoid tissues.

Introduction:
T helper 1 (T H 1) cells often accompany T H 17 cells across diverse tissues in health and disease, including the lungs. However, roles for the T H 1 effector cytokine, IFN-?, in T H 17-driven type 3 inflammation is unclear.

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