Type I IFN signaling impairs early M. tuberculosis control in both C57BL/6 and highly TB-susceptible C3HeB/FeJ mice. (a) C57BL/6 mice were aerosol infected with M. tuberculosis HN878 and received intraperitoneal injection of either anti-IFNAR (αIFNAR) or isotype control three times per week either between days −1 and 13 (†) or days −1 and 27 (‡). (b and c) CFU counts in lung tissue from either the (b) early (†) or (c) continuous (‡) αIFNAR treatment regimen. (d) Numbers of neutrophils (Ly6G^hiCD11b^hiCD45⁺), total and Ly6C⁻MHC-II⁺ MDMs (Siglec F⁻ Ly6G⁻ CD11b⁺CD64⁺MerTK⁺CD45⁺), and CD44⁺ CD62⁻ CD4⁺ T cells (CD3ε⁺CD45⁺) in lung tissue, as determined by flow cytometry. (e) C3HeB/FeJ mice were aerosol infected with M. tuberculosis HN878 and received intraperitoneal injection of either αIFNAR or isotype control three times per week between days −1 and 18. (f) CFU counts in lung tissue. (g) Numbers of neutrophils, total and Ly6C⁻ MHC-II⁺ MDMs, and CD44⁺CD62⁻ CD4⁺ T cells in lung tissue, as determined by flow cytometry. Points represent individual replicate mice with lines at the mean. Data are from single experiments with N = 4–5 mice per group and are representative of two independent experiments. Statistical analysis for CFU counts at day 26–28: unpaired t test. All other statistical analysis: two-way ANOVA with Holm–Sidak post hoc test. Actual adjusted P values are shown or: *, P < 0.05; **, P < 0.01; ****, P < 0.0001; ns, not significant.