Strong sustained type I IFN signaling acts cell intrinsically to impair IFNγ responses and cause tuberculosis susceptibility

<i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) causes over one million annual deaths, but most infected individuals never exhibit symptoms. Type I interferons (IFNs) have emerged as a major factor driving <i>Mtb</i> susceptibility, but how type I IFNs impair immunity to <i>Mtb</i> is a key unresolved question. Here we show that an early and primary effect of type I IFN during <i>Mtb</i> 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 <i>Mtb</i> susceptibility 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 <i>Mtb</i> susceptibility.