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

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 γδ 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. Competing Interest Statement The authors have declared no competing interest. Footnotes Manuscript re-formatted with clearer figure legends and figure references in the text. No changes to figures or supplementary materials. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE324265 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE324044 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE321718