Single-Cell Sequencing Reveals That CD4+ T Cells Eliminate Senescent Prostate Epithelium to Delay Progression of Benign Prostatic Hyperplasia

Abstract

Benign prostatic hyperplasia (BPH) is an age-related condition characterized by progressive prostate enlargement driven in part by the accumulation of senescent epithelial cells and their pro-inflammatory secretome. Using human single-cell RNA sequencing and laser capture microdissection, we identified C-X-C Motif Chemokine Ligand 13 (CXCL13) as a key chemokine secreted by senescent prostate epithelial cells. CXCL13 recruits CD4⁺ T cells via the C-X-C Chemokine Receptor Type 5 (CXCR5) receptor, facilitating immune recognition through human leukocyte antigen–DR isotype (HLA-DR) and promoting senescent cell clearance. Functional assays revealed that CD4⁺ cytotoxic T lymphocytes (CTLs) mediate this clearance, while regulatory T cells (Tregs) suppress it, forming a functional dichotomy. Immunohistochemistry, transwell migration, and co-culture assays confirmed this CXCL13–CXCR5–HLA-DR axis. In a testosterone-induced BPH mouse model, CXCL13 treatment enhanced CD4⁺ T cell infiltration and reduced epithelial senescence, while CD4⁺ T cell depletion reversed these effects. Single-cell transcriptomics in mice further validated increased CXCL13 expression and CD4⁺ T cell engagement. These findings uncover a critical immune surveillance mechanism in BPH and suggest that targeting the CXCL13–CD4⁺ T cell axis may offer a novel therapeutic strategy for age-related prostate enlargement.