Frontiers in immunology · 2026
Second-order regulation: IFN-γ suppresses IL-17A-mediated type 3 inflammation.
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Ravi Vijay Raaj, Maxfield Sophia H, Niszczak Emma N, Kim Hannah Y, Harlow Olivia S, Kakarla Anjali, Whitehead Kalyn D, Shenoy Anukul T
Аннотация
BACKGROUND: T helper 1 (TH1) cells often accompany TH17 cells across diverse tissues in health and disease, including the lungs. However, roles for the TH1 effector cytokine, IFN-γ, in TH17-driven type 3 inflammation is unclear.
METHODS: We devised a simplified reductionistic model to determine the role of IFN-γ in IL-17A-driven inflammation during Streptococcus pneumoniae (Spn) infection in vivo. Briefly, intratracheal instillation of Spn along with recombinant TNF-α and IL-17A was used to mimic rapid Spn-specific, TH17-driven, type 3 inflammation seen in lungs on memory recall infection with Spn. Co-instillation of recombinant IFN-γ was used to probe the role for this TH1 cell-derived effector cytokine in anti-Spn immune response. Immune cellularity in bronchoalveolar lavage (BAL) was used to determine impacts of IFN-γ on type 3 inflammation in murine airways. Mice sufficient for- or lacking- IFN-γ or STAT1 were used to assess the immunoregulatory functions of IFN-γ in vivo.
RESULTS: IFN-γ 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-γ on type 3 inflammation. We find that the impact of IFN-γ was dependent on the degree of type 3 inflammation such that IFN-γ's immunoregulatory role became more striking at lower concentrations of all the three cytokines. Of note, the immunoregulatory effect of IFN-γ against TH17-driven type 3 inflammation was also evident in physiologically relevant settings: while immunized wild type (WT) mice controlled lethal Spn infection, immunized IFN-γ 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-γ in immunized wild type mice) suggesting risk for immunopathology.
CONCLUSIONS: Our findings identify a distinct immunoregulatory mechanism that operates within non-lymphoid tissues, where IFN-γ limits IL-17A-mediated type 3 inflammation via STAT1. Thus, the frequent accompaniment of TH17 cells with TH1 cells may represent a conserved mechanism that restrains immunopathological potential of TH17-driven neutrophilic inflammation via STAT1 signaling in non-lymphoid tissues.
METHODS: We devised a simplified reductionistic model to determine the role of IFN-γ in IL-17A-driven inflammation during Streptococcus pneumoniae (Spn) infection in vivo. Briefly, intratracheal instillation of Spn along with recombinant TNF-α and IL-17A was used to mimic rapid Spn-specific, TH17-driven, type 3 inflammation seen in lungs on memory recall infection with Spn. Co-instillation of recombinant IFN-γ was used to probe the role for this TH1 cell-derived effector cytokine in anti-Spn immune response. Immune cellularity in bronchoalveolar lavage (BAL) was used to determine impacts of IFN-γ on type 3 inflammation in murine airways. Mice sufficient for- or lacking- IFN-γ or STAT1 were used to assess the immunoregulatory functions of IFN-γ in vivo.
RESULTS: IFN-γ 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-γ on type 3 inflammation. We find that the impact of IFN-γ was dependent on the degree of type 3 inflammation such that IFN-γ's immunoregulatory role became more striking at lower concentrations of all the three cytokines. Of note, the immunoregulatory effect of IFN-γ against TH17-driven type 3 inflammation was also evident in physiologically relevant settings: while immunized wild type (WT) mice controlled lethal Spn infection, immunized IFN-γ 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-γ in immunized wild type mice) suggesting risk for immunopathology.
CONCLUSIONS: Our findings identify a distinct immunoregulatory mechanism that operates within non-lymphoid tissues, where IFN-γ limits IL-17A-mediated type 3 inflammation via STAT1. Thus, the frequent accompaniment of TH17 cells with TH1 cells may represent a conserved mechanism that restrains immunopathological potential of TH17-driven neutrophilic inflammation via STAT1 signaling in non-lymphoid tissues.