Contribution of cytotoxic CD8 T cells, neutrophils and type 1 interferon signaling to hyperinflammatory pathology in HIV associated TB meningitis

Barnacle, J. R.; Bangani, N.; Slawinski, H.; Barrington, C.; Wilkinson, K. A.; Stek, C. J.; Lai, R.; Meintjes, G.; Robertson, B. D.; Gengenbacher, M.; Davis, A. G.; Barber, D. L.; O'Garra, A.; Wilkinson, R. J.

doi:10.64898/2026.03.10.710544

bioRxiv · 10.64898/2026.03.10.710544

Contribution of cytotoxic CD8 T cells, neutrophils and type 1 interferon signaling to hyperinflammatory pathology in HIV associated TB meningitis

Barnacle, J. R.·Bangani, N.·Slawinski, H.·Barrington, C.·Wilkinson, K. A.·Stek, C. J.·Lai, R.·Meintjes, G.·Robertson, B. D.·Gengenbacher, M.·Davis, A. G.·Barber, D. L.·O'Garra, A.·Wilkinson, R. J.

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Abstract

Immune dysregulation contributes to death and disability in tuberculous meningitis. People living with HIV have the least evidence that anti-inflammatory therapy improves the poor outcome. Improving therapy relies on a more refined understanding of the host immune response. Single-cell RNA sequencing of 188,983 CSF cells from 25 adults with HIV-associated TBM revealed a predominance of cytotoxic CD8 T cells with low cytokine expression. In microbiologically-confirmed TBM, there was greater cytotoxicity in T, NK and {gamma}{delta} cells, and higher type 1 interferon stimulation in T and B lymphocytes. Neutrophils expressed markers suggesting heightened cytokine stimulation, enhanced effector function, and IL-8-mediated neutrophil recruitment. In a longitudinal cohort, type 1 interferon signaling increased in blood and CSF following treatment initiation. Overall, findings indicate a hyper-inflammatory immune response in the CSF of HIV-associated TBM patients characterised by an accumulation of granzyme-rich cytotoxic CD8 T cells, highly activated neutrophils and host-detrimental type 1 interferon signaling.

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Barnacle, J. R., Bangani, N., Slawinski, H., Barrington, C., Wilkinson, K. A., Stek, C. J., Lai, R., Meintjes, G., Robertson, B. D., Gengenbacher, M., Davis, A. G., Barber, D. L., O'Garra, A., Wilkinson, R. J.. 2026-03-10. Contribution of cytotoxic CD8 T cells, neutrophils and type 1 interferon signaling to hyperinflammatory pathology in HIV associated TB meningitis. https://doi.org/10.64898/2026.03.10.710544

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