CD4⁺T cells are homeostatic regulators duringMtbreinfection

ABSTRACTImmunological priming – either in the context of prior infection or vaccination – elicits protective responses against subsequentMycobacterium tuberculosis(Mtb) infection. However, the changes that occur in the lung cellular milieu post-primaryMtbinfection 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 priorMtbinfection elicits a long-lasting protective response against subsequentMtbexposure and that the depletion of CD4+T cells prior toMtbrechallenge 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, mitigatingMtbdisease 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 limitMtbdisease.