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

Caouaille, M.; Fromont, L.; Shinkawa, T.; Faucher, M.; Abdul Hamid, A. I.; Mazeres, S.; Duverge, Y.; Lorreyte, Y.; Naser, E.; Behar, S. M.; Lefrancais, E.; Neyrolles, O.; Hudrisier, D.

doi:10.64898/2025.12.05.692491

bioRxiv · 10.64898/2025.12.05.692491

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

Caouaille, M.·Fromont, L.·Shinkawa, T.·Faucher, M.·Abdul Hamid, A. I.·Mazeres, S.·Duverge, Y.·Lorreyte, Y.·Naser, E.·Behar, S. M.·Lefrancais, E.·Neyrolles, O.·Hudrisier, D.

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Abstract

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 IFN{gamma}, 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. TeaserIn tuberculosis, excessive type I interferon signaling reshapes the lung environment, limiting T cell accumulation and motility within infected lesions.

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Caouaille, M., Fromont, L., Shinkawa, T., Faucher, M., Abdul Hamid, A. I., Mazeres, S., Duverge, Y., Lorreyte, Y., Naser, E., Behar, S. M., Lefrancais, E., Neyrolles, O., Hudrisier, D.. 2025-12-09. SP140 limits type I interferon-driven pathology, preserving T cell motility and promoting resistance in tuberculosis. https://doi.org/10.64898/2025.12.05.692491

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