Journal Article

PRMT5 Is Required for T Cell Survival and Proliferation by Maintaining Cytokine Signaling

Okumura, Mariko, Greene, Mark I., Nagai, Yasuhiro, Kambayashi, Taku, Tanaka, Yukinori

2020

Overview

Arginine methylation is a post-translational modification that regulates many biological processes. However, the role of arginine methylation in immune cells is not well studied. Here we report an essential role of protein arginine methyltransferase 5 (PRMT5) in T cell homeostasis and activation-induced expansion. Using T cell-specific PRMT5 conditional knockout mice, we found that PRMT5 is required for natural killer T (NKT) cell but not for conventional or regulatory T (Treg) cell development after the double positive (DP) stage in the thymus. In contrast, PRMT5 was required for optimal peripheral T cell maintenance, for the transition of naïve T cells to effector/memory phenotype, and for early T cell development before the DP stage in a cell-intrinsic manner. Accordingly, PRMT5-deleted T cells showed impaired IL-7-mediated survival and TCR-induced proliferation . The latter was more pronounced and attributed to reduced responsiveness to IL-2. Acute deletion of PRMT5 revealed that not only naïve but also effector/memory T cells were impaired in TCR-induced proliferation in a development-independent manner. Reduced expression of common γ chain (γc), a shared receptor component for several cytokines including IL-7 and IL-2, on PRMT5-deleted T cells may be in part responsible for the defect. We further showed that PRMT5 was partially required for homeostatic T cell survival but absolutely required for lymphopenic T cell expansion . Thus, we propose that PRMT5 is required for T cell survival and proliferation by maintaining cytokine signaling, especially during proliferation. The inhibition of PRMT5 may provide a novel strategy for the treatment of diseases where uncontrolled T cell activation has a role, such as autoimmunity.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animals / Arginine / arginine methylation / Autoimmunity / Bone marrow / Cell activation / Cell growth / Cell Proliferation / Cell Survival / Cells, Cultured / cytokine signaling / Cytokines - metabolism / Effector cells / Flow cytometry / Homeostasis / Immunologic Memory / Immunological memory / Immunology / Interleukin 2 / Interleukin 7 / Laboratories / Lungs / Lymphatic system / Lymphocyte Activation / Lymphocytes / Lymphocytes T / Lymphopenia / Memory cells / Methylation / Mice / Mice, Inbred C57BL / Mice, Knockout / Natural killer cells / Natural Killer T-Cells - physiology / Phenotypes / Post-translation / PRMT5 / Protein arginine methyltransferase / Protein-Arginine N-Methyltransferases - genetics / Protein-Arginine N-Methyltransferases - metabolism / Proteins / Signal Transduction / Spleen / T cell development / T cell proliferation / T cell receptors / T cell survival / T-Lymphocytes, Regulatory - immunology / Thymus gland / Transcription factors