Arginine methylation controls the strength of γc-family cytokine signaling in T cell maintenance

Inoue, Maia; Okamoto, Kazuo; Terashima, Asuka; Nitta, Takeshi; Muro, Ryunosuke; Negishi-Koga, Takako; Kitamura, Toshio; Nakashima, Tomoki; Takayanagi, Hiroshi

doi:10.1038/s41590-018-0222-z

Cited by 64 publications

(69 citation statements)

References 49 publications

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“…During preparation of this manuscript, a study investigating the role of PRMT5 in T cells was reported by (18). Similar to our study, the investigators generated a T-cell-specific PRMT5 conditional knockout mouse (CD4 Cre PRMT5 fl/ mice), which showed loss of iNKT cells in the thymus and T cell lymphopenia in the periphery.…”

Section: Discussionsupporting

confidence: 64%

“…Inoue et al have investigated the underlying mechanisms by which PRMT5 regulates γc cytokine signaling. They concluded that PRMT5 positively controls the expression of γc and JAK3 in activated T cells by promoting splicing via the arginine methylation of Sm proteins such as SmD3 (18). In agreement with these conclusions, a previous comprehensive study on arginine-methylated proteins in T cells identified altered arginine methylation occupancy in a subset of proteins involved in mRNA splicing during T cell stimulation (6).…”

Section: Discussionmentioning

confidence: 53%

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

et al. 2020

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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 in vitro. 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 PRMT5deleted 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.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 53%

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

et al. 2020

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“…Interestingly, loss of PRMT5 affected thymic cellularity, indicating a role for PRMT5 in early thymocyte development; however, no difference was seen in spleen weight or cellularity (20). T cell-specific deletion of PRMT5 results in defects in peripheral T cell maintenance as well as T cell signal transduction via splicing defects in γc and JAK3 mRNA (21). Our group has shown previously that PRMT5 blockade with a PRMT5 inhibitor suppresses memory T cell responses and reduces inflammation in experimental autoimmune encephalomyelitis mouse models (22).…”

Section: Introductionmentioning

confidence: 99%

PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease

Snyder¹,

Zitzer²,

Gao³

et al. 2020

JCI Insight

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“…Furthermore, there is an increasing awareness that protein argine methylation is critical for T lymphocyte activation (Inoue et al 2018). How do T cells 'manage' the increased demand for methyl donors as they respond to immune activation ?…”

Section: Introductionmentioning

confidence: 99%

“…There are many studies showing the importance of protein, RNA, DNA and histone methyltransferases in T cells (Inoue et al 2018;H.-B. Li et al 2017;Lee et al 2001; Thomas et al 2012;X.-P. Yang et al 2015;Karantanos et al 2016;Gray et al 2017;Sellars et al 2015;DuPage et al 2015;Geoghegan et al 2015;Zhang et al 2014;Tumes et al 2013;Gamper et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Antigen receptor control of methionine metabolism in T cells

Sinclair

Howden

Brenes-Murillo

et al. 2018

Preprint

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Immune activated T lymphocytes modulate the activity of key metabolic pathways to support the transcriptional reprograming and reshaping of cell proteomes that permits effector T cell differentiation. The present study uses high resolution mass spectrometry and metabolic labelling to explore how T cells control the methionine cycle to produce methyl donors for protein and nucleotide methylations. We show that antigen receptor engagement controls flux through the methionine cycle and also controls RNA and histone methylations. We establish that the main rate limiting step for the methionine cycle is control of methionine transporter expression by antigen receptors. Only T cells that respond to antigen to upregulate and sustain methionine transport are supplied with the methyl donors that permit the dynamic nucleotide methylations and epigenetic reprogramming that drives T cell differentiation.

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Arginine methylation controls the strength of γc-family cytokine signaling in T cell maintenance

Cited by 64 publications

References 49 publications

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

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

PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease

Antigen receptor control of methionine metabolism in T cells

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