GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE334nnn/GSE334520/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE334520GEOGSEfalseStrong sustained type I IFN signaling acts cell intrinsically to impair IFNγ responses and cause tuberculosis susceptibilityMycobacterium tuberculosis (Mtb) causes over one million deaths annually, but most infected individuals never exhibit symptoms. Type I interferons (IFNs) have emerged as a major factor driving susceptibility to Mtb, but how type I IFNs impair immunity to Mtb is a key unresolved question. Here we show that an early effect of type I IFN during Mtb infection is the cell-intrinsic impairment of IFNγ signaling. IFNγ 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 IFNγ signaling, and rescued susceptibility to Mtb 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 IFNγ to cause susceptibility to Mtb.2026/08/08GSE334520GSM9790259GSM9790270GSM9790271GSM9790260GSM9790272GSM9790261GSM9790262GSM9790263GSM9790264GSM9790265GSM9790266GSM9790255GSM9790256GSM9790267GSM9790268GSM9790257GSM9790269GSM979025815103334520Mus musculus