Distinct tissue niches contribute to prostate tissue-resident memory T cell differentiation and heterogeneity 2256438

Abstract Introduction The prostate is an exocrine organ, a barrier tissue to the male reproductive system, and a site of malignancy, yet prostate tissue-resident memory T cells and the unique cues in the tissue environment remain unexplored. Methods To study T cell memory formation in the prostate, we utilized acute systemic viral infection with lymphocytic choriomeningitis virus (LCMV) Armstrong, which has been used to study CD8+ tissue-resident memory T cells in a broad range of other tissues. To further characterize this population, we employed genetic mouse models, scRNA-seq and spatial transcriptomics to investigate antigen-specific prostate tissue-resident memory T cell formation, differentiation, and heterogeneity. Results Acute infection generated a population of long-lived CD8+ T cells with characteristics of tissue residency. These prostate tissue-resident memory T cells protect against reinfection and display functional and phenotypic heterogeneity in both mice and humans. Functional interrogation of TGFβ-, IL-7-, and IL-15-derived signals reveal subset-specific prostate tissue-resident memory T cell dependencies according to their niche-dependent phenotypes and distinct cytokine sources. For instance, tissue-resident memory-promoting cytokines IL-15 and TGFβ are highest in the prostate epithelium where CD8+ T cells are most enriched for tissue-resident memory-associated gene expression and analysis of human prostate samples identified similar patterns of both cytokine and CD8+ T cell localization. Conclusion We define a spatial framework of heterogenous T cell residence in the prostate, with prostate tissue-resident memory T cell heterogeneity being spatially segregated based on discrete cytokine and chemokine niches, with divergence of T cell transcriptional states between T cells localized to the stromal versus epithelial regions in both mice and humans Funding Source F31AI176705 Topic Categories Mucosal and Regional Immunology (MUC)