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Using bulk and scRNA-seq over the first weeks of infection, we describe an unexpected, higher early pulmonary type I IFN response in relatively resistant C57BL\/6 as compared with highly TB-susceptible C3HeB\/FeJ mice. C57BL\/6 mice showed pronounced early monocyte-derived macrophage (MDM) accumulation and extensive CD4+ T cell\u2013MDM interactions in lung lesions, accompanied by high expression of T cell\u2013attractant chemokines by MDMs. Conversely, lesions in C3HeB\/FeJ mice were dominated by neutrophils with high expression of pro-inflammatory chemokines, from which CD4+ T cells were spatially segregated. Early type I IFN signaling blockade reduced bacterial load and neutrophil swarming within early TB lesions while increasing CD4+ T cell numbers in both C57BL\/6 and C3HeB\/FeJ mice, with later more pronounced effects on bacterial load in C3HeB\/FeJ mice. These data suggest that early type I IFN signaling during M. tuberculosis infection favors neutrophil accumulation and limits CD4+ T cell infiltration into developing lesions.<\/jats:p>","DOI":"10.1084\/jem.20250466","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T14:37:57Z","timestamp":1758638277000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Type I IFN drives neutrophil swarming, impeding lung T cell\u2013macrophage interactions and TB control"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4353-4857","authenticated-orcid":true,"given":"William J.","family":"Branchett","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04tnbqb63","id-type":"ROR","asserted-by":"publisher"}],"name":"The Francis Crick Institute 1 Immunoregulation and Infection Laboratory, , 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