{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T06:09:38Z","timestamp":1778479778269,"version":"3.51.4"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["T32AI007413, T32AI007528"],"award-info":[{"award-number":["T32AI007413, T32AI007528"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R00HL157555"],"award-info":[{"award-number":["R00HL157555"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["T32TR004371"],"award-info":[{"award-number":["T32TR004371"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007270","name":"University of Michigan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007270","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      T helper 1 (T\n                      <jats:sub>H<\/jats:sub>\n                      1) cells often accompany T\n                      <jats:sub>H<\/jats:sub>\n                      17 cells across diverse tissues in health and disease, including the lungs. 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 simplified 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                    <\/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. We find that the impact of IFN-\u03b3 was dependent on the degree of type 3 inflammation such that IFN-\u03b3\u2019s immunoregulatory role became more striking at lower concentrations of all the three cytokines. Of note, 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 wild type (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 improved antimicrobial resistance, however, was accompanied by heightened airway neutrophilia (which could be phenocopied by mere neutralization of IFN-\u03b3 in immunized wild type mice) 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":"10.3389\/fimmu.2026.1744476","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T05:31:07Z","timestamp":1778477467000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Second-order regulation: IFN-\u03b3 suppresses IL-17A-mediated type 3 inflammation"],"prefix":"10.3389","volume":"17","author":[{"given":"Vijay Raaj","family":"Ravi","sequence":"first","affiliation":[{"name":"Dept. of Microbiology and Immunology, University of Michigan Medical School","place":["Ann Arbor, MI, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophia H.","family":"Maxfield","sequence":"additional","affiliation":[{"name":"Dept. of Microbiology and Immunology, University of Michigan Medical School","place":["Ann Arbor, MI, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma N.","family":"Niszczak","sequence":"additional","affiliation":[{"name":"Dept. of Microbiology and Immunology, University of Michigan Medical School","place":["Ann Arbor, MI, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah Y.","family":"Kim","sequence":"additional","affiliation":[{"name":"Dept. of Microbiology and Immunology, University of Michigan Medical School","place":["Ann Arbor, MI, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivia S.","family":"Harlow","sequence":"additional","affiliation":[{"name":"Dept. of Microbiology and Immunology, University of Michigan Medical School","place":["Ann Arbor, MI, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anjali","family":"Kakarla","sequence":"additional","affiliation":[{"name":"Dept. of Microbiology and Immunology, University of Michigan Medical School","place":["Ann Arbor, MI, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kalyn D.","family":"Whitehead","sequence":"additional","affiliation":[{"name":"Dept. of Microbiology and Immunology, University of Michigan Medical School","place":["Ann Arbor, MI, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anukul T.","family":"Shenoy","sequence":"additional","affiliation":[{"name":"Dept. of Microbiology and Immunology, University of Michigan Medical School","place":["Ann Arbor, MI, United States"]},{"name":"Dept. of Internal 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