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

J Immunol. 2022 Jan 15;208(2):501-513. doi: 10.4049/jimmunol.2100523. Epub 2021 Dec 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Carcinogenesis / genetics*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / pathology
  • Hematopoiesis / physiology
  • Lectins, C-Type / metabolism*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Lymphocyte Activation / immunology
  • Male
  • Methylation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Animal
  • Positive Regulatory Domain I-Binding Factor 1 / metabolism
  • Protein-Arginine N-Methyltransferases / deficiency*
  • Protein-Arginine N-Methyltransferases / genetics
  • RNA-Seq
  • Receptors, Immunologic / metabolism*
  • Signal Transduction / genetics
  • Single-Cell Analysis


  • Klrg1 protein, mouse
  • Lectins, C-Type
  • Prdm1 protein, mouse
  • Receptors, Immunologic
  • Positive Regulatory Domain I-Binding Factor 1
  • Prmt5 protein, mouse
  • Protein-Arginine N-Methyltransferases