Disseminated tuberculosis is associated with impaired T cell immunity mediated by non-canonical NF-κB pathway.

Objectives: The mechanism that leads to disseminated tuberculosis in HIV-negative patients is still largely unknown. T cell subsets and signaling pathways that were associated with disseminated tuberculosis were investigated.

Methods: Single-cell profiling of whole T cells was performed to identify T cell subsets and enriched signaling pathways that were associated with disseminated tuberculosis. Flow cytometric analysis and blocking experiment were used to investigate the findings obtained by transcriptome sequencing.

Results: Patients with disseminated tuberculosis had depleted Th1, Tc1 and Tc17 cell subsets, and IFNG was the most down-regulated gene in both CD4 and CD8 T cells. Gene Ontology analysis showed that non-canonical NF-κB signaling pathway, including NFKB2 and RELB genes, was significantly down-regulated and was probably associated with disseminated tuberculosis. Expression of several TNF superfamily ligands and receptors, such as LTA and TNF genes, were suppressed in patients with disseminated tuberculosis. Blocking of TNF-α and soluble LTα showed that TNF-α was involved in IFN-γ production and LTα influenced TNF-α expression in T cells.

Conclusions: Impaired T cell IFN-γ response mediated by suppression of TNF and non-canonical NF-κB signaling pathways might be responsible for disseminated tuberculosis.