CD4+ T cells re-wire granuloma cellularity and regulatory networks to promote immunomodulation following Mtb reinfection

Immunological priming—in the context of either 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. Using clinical and microbiological endpoints in a non-human primate reinfection model, we demonstrated that prior Mtb infection elicited a long-lasting protective response against subsequent Mtb exposure and was CD4⁺ T cell dependent. By analyzing data from primary infection, reinfection, and reinfection-CD4⁺ T cell-depleted granulomas, we found that the presence of CD4⁺ T cells during reinfection resulted in a less inflammatory lung milieu characterized by reprogrammed CD8⁺ T cells, reduced neutrophilia, and blunted type 1 immune signaling among myeloid cells. These results open avenues for developing vaccines and therapeutics that not only target lymphocytes but also modulate innate immune cells to limit tuberculosis (TB) disease.