Abstract
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 MOG(35-55)-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.
Highlights
Glycine N-methyltransferase (GNMT, EC 2.1.1.20) regulates the ratio of S-adenosylmethionine (SAM) toS-adenosylhomocysteine (SAH) and serves as a folate-binding protein [1,2]
Our results indicated that the percentages of CD69+CD4+ or CD69+CD8+ were similar between Gnmt–/– and wild-type mice, excluding the role of GNMT in T-cell activation type mice
Our results revealed that the kinetics of EAE progression was slightly attenuated in Gnmt–/– mice compared with wild-type mice (Figure 1B)
Summary
Glycine N-methyltransferase (GNMT, EC 2.1.1.20) regulates the ratio of S-adenosylmethionine (SAM) toS-adenosylhomocysteine (SAH) and serves as a folate-binding protein [1,2]. Since a high percentage of Gnmt–/– mice developed HCC, we hypothesized that GNMT deficiency may affect the immune surveillance system. Natural killer (NK) cells from Gnmt–/– mice were activated spontaneously, expressed more tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) and had stronger cytotoxic activity, suggesting that they contributed to a proinflammatory environment in the liver [13]. These lines of evidence indicate that GNMT is involved in the pathogenesis of inflammatory processes. Whether GNMT regulates the functions of CD4+ T-helper (Th) cell lineages is still unclear
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