Synergistic CD8+ T and CD4+ T cell concomitant immunity controls M. tuberculosis bacterial burden following M. tuberculosis reinfection in non-human primates 3013

Abstract Description Background The limited efficacy of the BCG vaccine for adult pulmonary Tuberculosis (TB), as well as rising drug resistance, underscores the need for new vaccines and treatments. Concomitant immunity provides strong protection against M. tuberculosis (Mtb) reinfection, but the underlying protective mechanisms have yet to be fully elucidated. Methods Single-cell RNA-seq of cynomolgus macaques with Mtb primary infection, reinfection, or reinfection with CD4+ or CD8+ T cell depletion was performed using Seq-Well S3. Data were integrated by scVI, cell types were annotated via marker genes and reference signatures. AUCell identified transcriptional signatures correlating with bacterial burden in granulomas. Results We profiled 180,117 cells from 92 granulomas and 39 lung tissues from 34 macaques. T/NK, B cells, and pDCs were negatively correlated with bacterial burden in reinfection granulomas, but not in primary infection or depletion cohorts. These correlations were lost with CD4+ or CD8+ T cell depletion, highlighting their roles in immune control against Mtb. Progenitor exhausted-like T cells (GZMKhigh Tpex), enriched in granulomas, exhibited a distinct phenotype relative to primary infection or depletion, correlating negatively with bacterial burden. Conclusions Both CD4+ and CD8+ T cells modulate T/NK, B, and pDC cell compartments in reinfection, with GZMKhigh Tpex-like cells acting as potential effectors for Mtb clearance. Insights may guide TB vaccine and therapy development. Funding Sources Supported by NIH IMPAc-TB (HI-IMPACT) Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)