ABSTRACT
Immunological priming – either in the context of prior infection or vaccination – elicits protective responses against subsequent Mycobacterium tuberculosis (Mtb) infection. However, the changes that occur in the lung cellular milieu post-primary Mtb infection and their contributions to protection upon reinfection remain poorly understood. Here, using clinical and microbiological endpoints in a non-human primate reinfection model, we demonstrate that prior Mtb infection elicits a long-lasting protective response against subsequent Mtb exposure and that the depletion of CD4+ T cells prior to Mtb rechallenge significantly abrogates this protection. Leveraging microbiologic, PET-CT, flow cytometric, and single-cell RNA-seq data from primary infection, reinfection, and reinfection-CD4+ T cell depleted granulomas, we identify differential cellular and microbial features of control. The data collectively demonstrate that the presence of CD4+ T cells in the setting of reinfection results in a reduced inflammatory lung milieu characterized by reprogrammed CD8+ T cell activity, reduced neutrophilia, and blunted type-1 immune signaling among myeloid cells, mitigating Mtb disease severity. These results open avenues for developing vaccines and therapeutics that not only target CD4+ and CD8+ T cells, but also modulate innate immune cells to limit Mtb disease.
Competing Interest Statement
A.K.S. reports compensation for consulting and/or scientific advisory board membership from Honeycomb Biotechnologies, Cellarity, Ochre Bio, Relation Therapeutics, FL86, IntrECate Biotherapeutics, Bio-Rad Laboratories, Senda Biosciences and Dahlia Biosciences unrelated to this work. S.M.F. reports compensation for board of directors membership from Oxford Nanopore unrelated to this work.
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