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However, roles for the T\n                    <jats:sub>H<\/jats:sub>\n                    1 effector cytokine, IFN-\u03b3, in T\n                    <jats:sub>H<\/jats:sub>\n                    17-driven type 3 inflammation is unclear.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>\n                    We devised a reductionistic model to determine the role of IFN-\u03b3 in IL-17A-driven inflammation during\n                    <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                    (\n                    <jats:italic>Spn<\/jats:italic>\n                    ) infection\n                    <jats:italic>in vivo.<\/jats:italic>\n                    Briefly, intratracheal instillation of\n                    <jats:italic>Spn<\/jats:italic>\n                    along with recombinant TNF-\u03b1 and IL-17A was used to mimic rapid\n                    <jats:italic>Spn<\/jats:italic>\n                    -specific, T\n                    <jats:sub>H<\/jats:sub>\n                    17-driven, type 3 inflammation seen in lungs on memory recall infection with\n                    <jats:italic>Spn<\/jats:italic>\n                    . Co-instillation of recombinant IFN-\u03b3 was used to probe the role for this T\n                    <jats:sub>H<\/jats:sub>\n                    1 cell-derived effector cytokine in anti-\n                    <jats:italic>Spn<\/jats:italic>\n                    immune response. Immune cellularity in bronchoalveolar lavage (BAL) was used to determine impacts of IFN-\u03b3 on type 3 inflammation in murine airways. Mice sufficient for- or lacking-IFN-\u03b3 or STAT1 were used to assess the immunoregulatory functions of IFN-\u03b3\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>\n                    IFN-\u03b3 promptly muted IL-17A-induced inflammatory cell accumulation in\n                    <jats:italic>Spn<\/jats:italic>\n                    -infected airways through a STAT1-dependent mechanism. Both female and male mice demonstrated similar anti-inflammatory effects of IFN-\u03b3 on type 3 inflammation. Notably, the impact of IFN-\u03b3 was more striking at lower cytokine concentrations. The immunoregulatory effect of IFN-\u03b3 against T\n                    <jats:sub>H<\/jats:sub>\n                    17-driven type 3 inflammation was also evident in physiologically relevant settings: while immunized wildtype (WT) mice controlled lethal\n                    <jats:italic>Spn<\/jats:italic>\n                    infection, immunized IFN-\u03b3 knockout mice exhibited even better\n                    <jats:italic>Spn<\/jats:italic>\n                    clearance. This heightened antimicrobial resistance, however, was accompanied by overt airway neutrophilia suggesting risk for immunopathology.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>\n                    Our findings identify a distinct immunoregulatory mechanism that operates within non-lymphoid tissues, where IFN-\u03b3 limits IL-17A-mediated type 3 inflammation via STAT1. Thus, the frequent accompaniment of T\n                    <jats:sub>H<\/jats:sub>\n                    17 cells with T\n                    <jats:sub>H<\/jats:sub>\n                    1 cells may represent a conserved mechanism that restrains immunopathological potential of T\n                    <jats:sub>H<\/jats:sub>\n                    17-driven neutrophilic inflammation via STAT1 signaling in non-lymphoid tissues.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.05.697792","type":"posted-content","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T18:10:16Z","timestamp":1767723016000},"source":"Crossref","is-referenced-by-count":1,"title":["Second-order regulation: IFN-\u03b3 suppresses IL-17A-mediated neutrophilic inflammation"],"prefix":"10.64898","author":[{"given":"Vijay Raaj","family":"Ravi","sequence":"first","affiliation":[{"name":"Dept. of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, 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