Molecular Medicine

, Volume 20, Issue 1, pp 684–696 | Cite as

Role of Glycine N-Methyltransferase in the Regulation of T-Cell Responses in Experimental Autoimmune Encephalomyelitis

  • Chung-Hsien Li
  • Ming-Hong Lin
  • Shih-Han Chu
  • Pang-Hsien Tu
  • Cheng-Chieh Fang
  • Chia-Hung Yen
  • Peir-In Liang
  • Jason C. Huang
  • Yu-Chia Su
  • Huey-Kang Sytwu
  • Yi-Ming Arthur Chen
Research Article


Glycine N-methyltransferase (GNMT) is known for its function as a tumor suppressor gene. Since 100% of female Gnmt−/− mice developed hepatocellular carcinoma, we hypothesized that Gnmt−/− mice may have defective immune surveillance. In this study, we examined the immune modulation of GNMT in T-cell responses using experimental autoimmune encephalomyelitis (EAE). The results showed that EAE severity was reduced significantly in Gnmt−/− mice. Pathological examination of the spinal cords revealed that Gnmt−/− mice had significantly lower levels of mononuclear cell infiltration and demyelination than the wild-type mice. In addition, quantitative real-time PCR showed that expression levels of proinflammatory cytokines, including interferon (IFN)-γ and interleukin (IL)-17A, were much lower in the spinal cord of Gnmt−/− than in that of wild-type mice. Accordingly, myelin oligodendrocyte glycoprotein (MOG)-specific T-cell proliferation and induction of T-helper (Th)1 and Th17 cells were markedly suppressed in MOG35–55-induced Gnmt−/− mice. Moreover, the number of regulatory T (Treg) cells was increased significantly in these mice. When the T-cell receptor was stimulated, the proliferative capacity and the activation status of mTOR-associated downstream signaling were decreased significantly in Gnmt−/− CD4+ T cells via an IL-2- and CD25-independent manner. Moreover, GNMT deficiency enhanced the differentiation of Treg cells without affecting the differentiation of Th1 and Th17 cells. Furthermore, the severity of EAE in mice adoptive transferred with GNMT-deficient CD4+ T cells was much milder than in those with wild-type CD4+ T cells. In summary, our findings suggest that GNMT is involved in the pathogenesis of EAE and plays a crucial role in the regulation of CD4+ T-cell functions.



This study was supported partially by Kaohsiung Medical University Aim for the Top Universities Grant, KMU-TP103E00 and KMU-TP103E09; Aim for the Top 500 Universities Grant, DT103009; NSYSU-KMU JOINT RESEARCH PROJECT, NSYSUKMU103-I010; Progam to Upgrade the R&D Capabilities of Private Universities Grant, MOST103-2632-B-037-001; and Health and Welfare Surcharge of Tobacco Products, Ministry of Health and Welfare Grant, MOHW103-TD-B-111-05. We thank Chuen-Miin Leu for providing reagents, Marcelo Chen for revising the English writing and the staff from the Center of Infectious Disease and Cancer Research (CICAR) of Kaohsiung Medical University for technical assistance.

Supplementary material

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Authors and Affiliations

  • Chung-Hsien Li
    • 1
    • 2
  • Ming-Hong Lin
    • 3
  • Shih-Han Chu
    • 1
    • 2
  • Pang-Hsien Tu
    • 4
  • Cheng-Chieh Fang
    • 1
    • 2
  • Chia-Hung Yen
    • 2
    • 5
  • Peir-In Liang
    • 6
  • Jason C. Huang
    • 7
  • Yu-Chia Su
    • 8
  • Huey-Kang Sytwu
    • 3
  • Yi-Ming Arthur Chen
    • 2
    • 9
    • 10
    • 11
  1. 1.Institute of Microbiology and ImmunologyNational Yang-Ming UniversityTaipeiTaiwan
  2. 2.Center for Infectious Disease and Cancer Research (CICAR)Kaohsiung Medical UniversityKaohsiung CityTaiwan
  3. 3.Department and Graduate Institute of Microbiology and ImmunologyNational Defense Medical CenterTaipeiTaiwan
  4. 4.Institute of Biomedical SciencesAcademia SinicaTaipeiTaiwan
  5. 5.Graduate Institute of Natural Products, College of PharmacyKaohsiung Medical UniversityKaohsiungTaiwan
  6. 6.Department of Pathology, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiungTaiwan
  7. 7.Department of Biotechnology and Laboratory Science in MedicineNational Yang-Ming UniversityTaipeiTaiwan
  8. 8.National Applied Research LaboratoriesNational Laboratory Animal CenterTaipeiTaiwan
  9. 9.Institute of Biomedical SciencesNational Sun Yat-sen UniversityKaohsiungTaiwan
  10. 10.Department of Microbiology and Immunology, Institute of Medical Research and Institute of Clinical Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  11. 11.Kaohsiung CityTaiwan

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