Lethal Mtb dissemination occurre in the combined absence of lymhocytes and is independent of innate immune response

About two billion people are latently infected with Mycobacterium tuberculosis (Mtb), which can reside in multiple organs, including the lymphatics. The risk of latent Mtb infection (LTBI) reactivation increases with immunosuppression, such as HIV coinfection, yet the immunological correlates that maintain LTBI remain largely elusive. Using a mouse model of contained lymphatic Mtb infection we dissect the drivers of containment versus reactivation. We show that immunosuppression-induced dissemination of lymphatic Mtb and ensuing progressive disease can be prevented by vaccination with BCG or recombinant BCG even in the absence of CD4+ T cells. Multi-parameter imaging, spatial transcriptomics and network analysis reveal that anti-CD4-mediated immunosuppression triggers distinct repositioning of non-CD4 immune cells at the edge of TB lesions in cervical lymph nodes. Although B cell numbers increase, they prove dispensable for Mtb containment during CD4+ T cell loss. Using immune cell-deficient mice, cell depletion and adoptive transfers, we reveal that CD8+ T cells mediate vaccination-induced prevention of Mtb dissemination in the absence of CD4+ T cells, informing LTBI management in immunocompromised individuals. Overall design: To experimentally address the role of these cells for lymphatic LTBI containment, we induced lymphatic Mtb infection in a variety of genetically modified mouse strains with and without vaccination. First, we infected wild-type C57BL/6 mice, B6.muMT-/- mice that lack mature B cells 48, B6.Rag1-/- mice that lack mature B and T cells 49 and B6.Rag2-/-Il2rg-/- mice that lack mature B, T and NK cells 50 i.d. with Mtb. Two groups of C57BL/6 mice received anti-CD4 mAb treatment either alone or in addition to Mtb infection and naïve mice were also included as controls.3- 5 mice per group.