Abstract
CD8 (+) T cells are robustly activated during tuberculosis but how their responses differ in susceptible hosts remains unclear. Using mice lacking the transcriptional repressor Sp140, we assessed the magnitude and diversity of pulmonary CD8⁺ T cell responses to Mycobacterium tuberculosis infection. We show that control mice develop a robust CD8 (+) T cell response following infection, characterized by a diverse pool of effector and memory subsets and strong TNF and IFNγ production, whereas Sp140 (-/-) mice display a profound reduction in T cell numbers across all subsets. Single-cell RNA sequencing revealed redistribution and skewing of CD8 (+) T cell clusters in Sp140 (-/-) mice, with overrepresentation of gene expression programs associated with exhaustion and type I interferon (IFN-I) signaling. Blockade of the IFN-I receptor (IFNAR) restored CD8 (+) T cell numbers, diversity, cytokine production, spatial localization, and coincided with substantially reduced bacterial burden and lung pathology. Similarly, CD4 (+) T cell numbers were also rescued. 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. Together, these findings reveal that SP140 sustains host resistance in mice by restraining IFN-I-driven pathology, coinciding with preserved T cell immunity and lesion surveillance.