Molecular Medicine 2014

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, and Yi-Ming Arthur Chen

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.

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Posted by Sheila Platt on Mar 24, 2015 1:28 PM CDT