SP140 limits type I interferon-driven pathology, preserving T cell motility and promoting resistance in tuberculosis.

CD8T 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 toinfection. We show that control mice develop a robust CD8T cell response following infection, characterized by a diverse pool of effector and memory subsets and strong TNF and IFNγ production, whereasmice display a profound reduction in T cell numbers across all subsets. Single-cell RNA sequencing revealed redistribution and skewing of CD8T cell clusters inmice, with overrepresentation of gene expression programs associated with exhaustion and type I interferon (IFN-I) signaling. Blockade of the IFN-I receptor (IFNAR) restored CD8T cell numbers, diversity, cytokine production, spatial localization, and coincided with substantially reduced bacterial burden and lung pathology. Similarly, CD4T 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.