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

Nature Immunology volume 19, pages 1265–1276 (2018)Cite this article

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Abstract

The methylation of arginine residues in proteins is a post-translational modification that contributes to a wide range of biological processes. Many cytokines involved in T cell development and activation utilize the common cytokine receptor γ-chain (γc) and the kinase JAK3 for signal transduction, but the regulatory mechanism that underlies the expression of these factors remains unclear. Here we found that the arginine methyltransferase PRMT5 was essential for the maintenance of invariant natural killer T cells (iNKT cells), CD4+ T cells and CD8+ T cells. T cell–specific deletion of Prmt5 led to a marked reduction in signaling via γc-family cytokines and a substantial loss of thymic iNKT cells, as well as a decreased number of peripheral CD4+ T cells and CD8+ T cells. PRMT5 induced the symmetric dimethylation of Sm proteins that promoted the splicing of pre-mRNA encoding γc and JAK3, and this critically contributed to the expression of γc and JAK3. Thus, arginine methylation regulates strength of signaling via γc-family cytokines by facilitating the expression of signal-transducing components.

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Fig. 1: PRMT5 expression and symmetric arginine dimethylation in T cells.
Fig. 2: T cell–specific deletion of PRMT5 causes a decrease in iNKT cells, CD4+ T cells and CD8+ T cells.
Fig. 3: Cell-autonomous function for PRMT5 in the regulation of iNKT cells, CD4+ T cells and CD8+ T cells.
Fig. 4: PRMT5 is required for γc expression in iNKT cells.
Fig. 5: Impaired survival and proliferation of PRMT5-deficient peripheral T cells.
Fig. 6: PRMT5 regulates signaling via γc-family cytokines by promoting the expression of γc and JAK3.
Fig. 7: PRMT5 facilitates splicing of pre-mRNA from Il2rg and Jak3.

Data availability

The data that support the findings of this study are available from the corresponding author upon request. The RNA-seq data have been deposited in GEO with accession code GSE118135.

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Acknowledgements

We thank S. Hori (University of Tokyo) for pMSCV-Foxp3-IG; H. Kawamoto (Kyoto University) and T. Ikawa (Tokyo University of Science) for Tst4-DLL4 stromal cells; and C. Tsuda, T. Ono, K. Hamada, K. Kaneki, T. Suda, M. Tsukasaki, A. Suematsu, S. Sawa, N. Komatsu and Y. Nakayama for discussions and technical assistance. This work was supported in part by a grant for the ERATO Takayanagi Osteonetwork Project from the Japan Science and Technology Agency, and Grants-in-Aid for Specially Promoted Research (15H05703), Scientific Research (B) (16H05202 and 18H02919), Young Scientists (A) (15H05653), Young Scientists (B) (16K19102) and JSPS Research Fellow (15J05761) from the Japan Society for the Promotion of Science (JSPS). M.I. was supported by a JSPS Research Fellowship for Young scientists (15J05761).

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Authors and Affiliations

  1. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

    Maia Inoue, Takeshi Nitta, Ryunosuke Muro & Hiroshi Takayanagi

  2. Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

    Kazuo Okamoto & Asuka Terashima

  3. Department of Pharmacology, Showa University School of Dentistry, Shinagawa-ku, Tokyo, Japan

    Takako Negishi-Koga

  4. Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan

    Toshio Kitamura

  5. Division of Stem Cell Signaling, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan

    Toshio Kitamura

  6. Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

    Tomoki Nakashima

  7. JST, Precursory Research for Embryonic Science and Technology (PRESTO), Bunkyo-ku, Tokyo, Japan

    Tomoki Nakashima

  8. Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Bunkyo-ku, Tokyo, Japan

    Tomoki Nakashima

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Contributions

M.I. performed most of the experiments, interpreted the results and prepared the manuscript; K.O. provided advice on project planning and data interpretation and contributed to experiments of Il2rg splicing and manuscript preparation; A.T., T. Nitta and T.N.-K. contributed to data interpretation and discussions; R.M. performed retroviral transduction into thymocytes and contributed to data interpretation; T.K. provided a retroviral vector and advice on data analysis; T. Nakashima generated genetically modified mice and provided advice on data analysis; and H.T. directed the project and wrote the manuscript.

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Correspondence to Hiroshi Takayanagi.

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The Department of Osteoimmunology (of The University of Tokyo) is an endowed department supported by an unrestricted grant from Chugai Pharmaceutical Co., AYUMI Pharmaceutical Corporation and Noevir Co.

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Supplementary Figure 1 PRMT5 expression in T-cell subsets in the thymus and spleen.

(a) Prmt5 mRNA expression in CD4SP, CD8SP and iNKT cells in the thymus, and Treg, naïve CD4+ T and naïve CD8+ T cells in the spleen and lymph nodes, and activated CD4+ T and activated CD8+ T cells of Foxp3hCD2 knock-in mice (n = 3). Treg cells were isolated as CD4+CD25+hCD2+ T cells. T cells stimulated with anti-CD3/CD28 in the presence of IL-2 for 2 days were used as activated T cells. The level of mRNA expression was normalized with that of Actb mRNA expression. (b) Protein expression level of PRMT5 in thymocytes, naïve T cells and activated T cells. n = 2-4. (c) Prmt5 mRNA expression in CD4SP, CD8SP, iNKT and Treg cells in the thymus of Foxp3hCD2 knock-in mice (n = 3). Statistical analysis was carried out using One-way ANOVA with Tukey’s multiple-comparison test. *P < 0.05; **P < 0.01. Data are mean ± s.e.m. and representative of more than 2 independent experiments.

Supplementary Figure 2 Conditional gene-targeting of Prmt5.

(a) The targeting strategy to generate Prmt5 conditional mutant mice. The genomic structure of the wild-type Prmt5 gene is indicated. Exon 2 and 3 are flanked by loxP sequences; the Neo cassette is flanked by frt sequences. The modified Prmt5 locus after homologous recombination (Prmt5floxNeo allele) as well as the deleted Prmt5 gene after Cre-mediated excision of exons 2 and 3 (Prmt5Δ allele) are shown. The arrows below the diagram of the wild-type allele indicate the positions of the primers (P1, P2 and P3) used for the PCR genotyping. (b) The expression of Prmt5 mRNA in DN, DP, CD4SP and CD8SP cells of control (n = 3) and Prmt5flox/Δ Cd4-Cre (DN, n = 4; DP and CD4SP, n = 5; and CD8SP, n = 3) mice. (c) The number of TCRβ+ cells in the lymph nodes (control, n = 3; Prmt5flox/Δ Cd4-Cre, n = 6), liver (n = 7) and bone marrow (control, n = 3; Prmt5flox/Δ Cd4-Cre, n = 4). Statistical analysis was carried out using two-tailed Student’s t-test. NS, not significant (P > 0.05); *P < 0.05; ***P < 0.005. Data are mean ± s.e.m.

Supplementary Figure 3 Analysis of thymic iNKT cell development and the activation state of peripheral CD4+ and CD8+ T cells of Prmt5flox/Δ Cd4-Cre mice.

(a) The frequency of CD45.1+ cells and CD45.2+ cells in DP, CD4SP, CD8SP and iNKT cells in the thymus (n = 4), and splenic B cells (n = 3) of BM chimeric mice. Each line indicates individual mice. Prmt5flox/Δ Cd4-Cre BM cells were able to develop into DP cells, SP cells and B cells similarly to control BM cells. (b) CD1d expression on DP cells of control (n = 5) and Prmt5flox/Δ Cd4-Cre (n = 3) mice. The bar graphs show the mean fluorescence intensity (MFI) of CD1d. (c) The frequencies of CD62L+CD44–, CD62L–CD44+ and CD62L+CD44+ cells among CD4+ T and CD8+ T cells in the spleen of control and Prmt5flox/Δ Cd4-Cre mice. (d) The frequencies of CD44+ cells in CD4+ T and CD8+ T cells of control (n = 8) and Prmt5flox/Δ Cd4-Cre (n = 10) mice. (e) Va14-Ja18 transcripts in pre-selected (CD69loTCRβlo) DP cells of control and Prmt5flox/Δ Cd4-Cre mice (n = 3). Statistical analysis was carried out using two-tailed Student’s t-test. NS, not significant (P > 0.05); *P < 0.05; ***P < 0.005. Data are mean ± s.e.m. and representative of more than 2 independent experiments.

Supplementary Figure 4 Carm1 and Prmt9 expression in thymic Treg cells and effects of retroviral transduction of Foxp3 on Prmt5 expression.

(a) The expression of Carm1 and Prmt9 was measured in iNKT and Treg cells in the thymus, and Treg and naïve CD4+ T cells in the spleen and lymph nodes of Foxp3hCD2 knock-in mice (n = 4). Treg cells were isolated as CD4+CD25+hCD2+ T cells. (b, c) Effects of retroviral expression of Foxp3 on Prmt5 expression in thymocytes (n = 6) (a) and peripheral CD4+ T cells (n = 3) (b). Statistical analysis was carried out using One-way ANOVA with Tukey’s multiple-comparison test (a) and two-tailed Student’s t-test (b,c). *P < 0.05; **P < 0.01; ***P < 0.005. Data are mean ± s.e.m. and representative of 2 independent experiments.

Supplementary Figure 5 Retroviral expression of a constitutively active form of STAT5 rescued impaired expression of CD25 in PRMT5-deficient T cells.

Effects of retroviral expression of a constitutively active form of STAT5 (STAT5A1*6) on CD25 expression in CD4+ and CD8+ T cells (n = 3). Empty: empty vector. Statistical analysis was carried out using two-tailed Student’s t-test. NS, not significant (P > 0.05); *P < 0.05; **P < 0.01. Data are mean ± s.e.m.

Supplementary Figure 6 Effects of the disruption of the Prmt5 gene on the splicing of Il2rg and Jak3 pre-mRNA.

(a) A procedure to analyze genes, the splicing of which was affected in PRMT5-deficient stage 1 iNKT cells. Ninety-five genes were arranged in the order of fold change in intron ratio and the top 30 genes were listed. The Il2rg and Jak3 genes ranked 16th and 22nd, respectively. (b) Schematic diagram of γc mRNA splice isoforms. The arrows indicate a primer set specifically targeting membrane γc or soluble γc. (c) mRNA expression of soluble γc in control (n = 4-9) and PRMT5-deficient (n = 4-9) T cells. (d) Subcloning and sequencing of the PCR products amplified by primers targeting exon 1 and exon 8 of the Il2rg gene in activated T cells of control and PRMT5-deficient mice (n = 1). Transcripts retaining intron 3, introns 3 and 5, and introns 3, 5 and 6, as well as a transcript skipping exon 6 were detected in PRMT5-deficient T cells. (e) Effects of retroviral expression of γc and JAK3 on surface expression of human γc in 7AAD–CD4+ T cells of control (n = 5) and Prmt5flox/Δ Cd4-Cre mice (n = 4). Empty: empty vector. The number shows the mean fluorescence intensity (MFI) of human γc. (f) The ratio of the unspliced mRNA to spliced mRNA in each intron of the Il2rg gene in naïve CD4+ T (control, n = 4; Prmt5flox/Δ Cd4-Cre, n = 5) and CD8+ T cells (control, n = 6; Prmt5flox/Δ Cd4-Cre, n = 7). (g) mRNA expression of soluble γc in naïve CD4+ T (control, n = 4; Prmt5flox/Δ Cd4-Cre, n = 5) and CD8+ T cells (control, n = 6; Prmt5flox/Δ Cd4-Cre, n = 7) Statistical analysis was carried out using two-tailed Student’s t-test. NS, not significant (P > 0.05); *P < 0.05; **P < 0.01; ***P < 0.005. Data are mean ± s.e.m. and representative of 2 independent experiments.

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Inoue, M., Okamoto, K., Terashima, A. et al. Arginine methylation controls the strength of γc-family cytokine signaling in T cell maintenance. Nat Immunol 19, 1265–1276 (2018). https://doi.org/10.1038/s41590-018-0222-z

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