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Type I interferons (IFNs) have emerged as a major factor driving susceptibility to\n                  <jats:italic>Mtb<\/jats:italic>\n                  , but how type I IFNs impair immunity to\n                  <jats:italic>Mtb<\/jats:italic>\n                  is a key unresolved question. Here we show that an early effect of type I IFN during\n                  <jats:italic>Mtb<\/jats:italic>\n                  infection is the cell-intrinsic impairment of IFN\u03b3 signaling. IFN\u03b3 signaling was selectively impaired in the subset of infected macrophages experiencing high and sustained levels of type I IFN signaling. Genetic elimination of RESIST, a recently described positive regulator of type I IFN production, specifically eliminated the high and sustained type I IFN response, fully restored IFN\u03b3 signaling, and rescued susceptibility to\n                  <jats:italic>Mtb<\/jats:italic>\n                  without affecting basal type I IFN responses. Our results demonstrate that strong and sustained type I IFN responses specifically and cell intrinsically impair responsiveness to IFN\u03b3 to cause susceptibility to\n                  <jats:italic>Mtb<\/jats:italic>\n                  .\n                <\/jats:p>","DOI":"10.64898\/2026.01.19.700487","type":"posted-content","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T02:45:15Z","timestamp":1769136315000},"source":"Crossref","is-referenced-by-count":2,"title":["Strong sustained type I IFN signaling acts cell intrinsically to impair IFN\u03b3 responses and cause tuberculosis susceptibility"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4899-4414","authenticated-orcid":false,"given":"Stefan A.","family":"Fattinger","sequence":"first","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Parisi","sequence":"additional","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto A.","family":"Chavez","sequence":"additional","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA"},{"name":"Howard Hughes Medical Institute, University of California, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian R.","family":"Fairgrieve","sequence":"additional","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA"},{"name":"Howard Hughes Medical Institute, University of California, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ophelia V.","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen C.","family":"Witt","sequence":"additional","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse J.","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA"},{"name":"Howard Hughes Medical Institute, University of California, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Turcotte","sequence":"additional","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ella C.","family":"Brydon","sequence":"additional","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA"},{"name":"Howard Hughes Medical Institute, University of California, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harmandeep","family":"Dhaliwal","sequence":"additional","affiliation":[{"name":"Cancer Research Laboratory, University of California, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angus Y.","family":"Lee","sequence":"additional","affiliation":[{"name":"Cancer Research Laboratory, University of California, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7843-1503","authenticated-orcid":false,"given":"Dmitri I.","family":"Kotov","sequence":"additional","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA"},{"name":"Division of Infectious Diseases, Department of Medicine, Andrew M. and Jane M. 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