Type I IFN drives neutrophil swarming, impeding lung T cell-macrophage interactions and TB control.

The early immune mechanisms determining Mycobacterium tuberculosis infection outcome are unclear. 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-MDM interactions in lung lesions, accompanied by high expression of T cell-attractant 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.