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

Immune dysregulation contributes to death and disability in tuberculous meningitis. People living with HIV have the highest risk of TBM, greatest death and disability, and the least evidence that anti-inflammatory therapy improves the poor outcome. Improving therapy relies on a more refined understanding of the host immune response. Using single cell RNA sequencing, we characterised 188,983 lumbar CSF cells from 25 adults with HIV-associated TBM and identified correlates of bacterial load. There was heterogeneity in cell composition between patients, but cytotoxic CD8 T cells with low cytokine expression were consistently predominant with a large number expressing GZMK, known to activate complement. 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 peripheral neutrophil recruitment. In a separate longitudinal cohort, type 1 interferon signaling increased in the 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 IFN signaling.