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. [Display omitted] • CD4+ T cells are required for protection against Mtb reinfection in macaques • Mtb reinfection promotes immuno-modulatory CD8+ T cell-biased immunity • Myeloid-derived cells downregulate gene networks implicated in TB susceptibility • Self-reinforcing cellular circuits balance host immunity in reinfection granulomas Th1 CD4+ T cells mediate protective anti- Mtb immunity across biological systems and organisms. Bromley, Ganchua, et al. demonstrate that CD4+ T cells regulate immune tone in TB granulomas and are necessary for immune recall and protection against reinfection. Following reinfection, CD4+ T cells facilitate the development of a growth restrictive niche via the induction of immuno-modulatory genes and cellular interaction networks. [ABSTRACT FROM AUTHOR]