Y chromosome gene KDM5D coordinates epigenetic and metabolic control of sex differences in CD8⁺ T cell immunity [RNA-seq]

Here, we combine murine colorectal cancer (CRC) models, primary CD8+ T-cell perturbation studies, and single-cell transcriptomic analyses of human CRC to define a male-biased regulatory axis that limits CD8+ T-cell effector function. Male CD8+ T cells displayed reduced cytokine production, proliferation, cytotoxicity, TCR abundance, and TCR signaling relative to female CD8+ T-cells.

Mechanistically, depletion of histone demethylase KDM5D, encoded by the Y chromosome, enhanced TCR expression and clustering, increased proximal TCR signaling, reduced cholesterol biosynthetic programs, and lowered expression of exhaustion-associated genes. In human CRC single-cell datasets, male tumor-infiltrating CD8+ T-cells showed enrichment for exhaustion and cholesterol-associated programs, supporting the translational relevance of this axis.