1. PRMT5 Is Required for T Cell Survival and Proliferation by Maintaining Cytokine Signaling
- Author
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Mariko Okumura, Yasuhiro Nagai, Mark I. Greene, Yukinori Tanaka, and Taku Kambayashi
- Subjects
0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,Protein-Arginine N-Methyltransferases ,Cell Survival ,medicine.medical_treatment ,T cell ,Cell ,Immunology ,Biology ,Lymphocyte Activation ,T-Lymphocytes, Regulatory ,T cell proliferation ,T cell survival ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,medicine ,Immunology and Allergy ,Animals ,Homeostasis ,Receptor ,Cells, Cultured ,Original Research ,Cell Proliferation ,Mice, Knockout ,Effector ,Cell growth ,Protein arginine methyltransferase 5 ,T cell development ,Cell biology ,arginine methylation ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,Cytokines ,Natural Killer T-Cells ,PRMT5 ,cytokine signaling ,lcsh:RC581-607 ,Immunologic Memory ,030215 immunology ,Signal Transduction - Abstract
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 naive 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 in vitro. The latter was more pronounced and attributed to reduced responsiveness to IL-2. Acute deletion of PRMT5 revealed that not only naive 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 in vivo. 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.
- Published
- 2020
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