Type I interferon–driven lung pathology restricts T cell accumulation and motility during tuberculosis

CD8 + T cells are elicited during tuberculosis yet how susceptible lung environments shape their maintenance and behavior is unclear. We examined pulmonary T cell responses to Mycobacterium tuberculosis in resistant control and Sp140 -/- mice, a model of type I interferon (IFN-I)-driven susceptibility. Resistant mice generated diverse CD8 + effector- and memory-like subsets producing TNF and IFNγ, whereas Sp140 -/- mice showed a broad loss of pulmonary CD8 + T cells. Single-cell RNA sequencing revealed altered states in CD8 + T cells from susceptible mice with exhaustion and IFN-I transcriptional programs. IFNAR blockade rescued CD8 + T cell numbers, diversity, cytokine production, reduced bacterial burden and lung pathology, with comparable benefits also valid for CD4 + T cells. Intravital microscopy of infected lungs further showed that T cell dynamics and motility within lesions were restricted under exuberant IFN-I signaling but fully restored by IFNAR blockade. Thus, IFN-I-driven tissue pathology restricts T cell accumulation and motility during tuberculosis. Teaser In tuberculosis, excessive type I interferon signaling reshapes the lung environment, limiting T cell accumulation and motility within infected lesions.