PRMT5 Deficiency Enforces the Transcriptional and Epigenetic Programs of Klrg1⁺CD8⁺ Terminal Effector T Cells and Promotes Cancer Development

Protein arginine methyltransferase 5 (PRMT5) participates in the symmetric dimethylation of arginine residues of proteins and contributes to a wide range of biological processes. However, how PRMT5 affects the transcriptional and epigenetic programs involved in the establishment and maintenance of T cell subset differentiation and roles in antitumor immunity is still incompletely understood. In this study, using single-cell RNA and chromatin immunoprecipitation sequencing, we found that mouse T cell-specific deletion of PRMT5 had greater effects on CD8(+) than CD4(+) T cell development, enforcing CD8(+) T cell differentiation into Klrg1(+) terminal effector cells. Mechanistically, T cell deficiency of PRMT5 activated Prdm1 by decreasing H4R3me2s and H3R8me2s deposition on its loci, which promoted the differentiation of Klrg1(+)CD8(+) T cells. Furthermore, effector CD8(+) T cells that transited to memory precursor cells were decreased in PRMT5-deficient T cells, thus causing dramatic CD8(+) T cell death. In addition, in a mouse lung cancer cell line-transplanted tumor mouse model, the percentage of CD8(+) T cells from T cell-specific deletion of PRMT5 mice was dramatically lost, but CD8(+)Foxp3(+) and CD8(+)PDL1(+) regulatory T cells were increased compared with the control group, thus accelerating tumor progression. We further verified these results in a mouse colon cancer cell line-transplanted tumor mouse model. Our study validated the importance of targeting PRMT5 in tumor treatment, because PRMT5 deficiency enforced Klrg1(+) terminal CD8(+) T cell development and eliminated antitumor activity.