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Inhibition of Transmethylation Down-Regulates CD4 T Cell Activation and Curtails Development of Autoimmunity in a Model System

Brian R. Lawson^1,*, Yulia Manenkova^*, Jasimuddin Ahamed, Xiaoru Chen^*, Jian-Ping Zou, Roberto Baccala, Argyrios N. Theofilopoulos and Chong Yuan^*

^* Diazyme Laboratories Division, General Atomics, San Diego, CA 92186; Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; and Shanghai Institute of Materia Medica, Shanghai, China

Transmethylation affects several cellular events, including T cell activation, and blockade of this pathway may curtail inflammatory/autoimmune responses. Here, we demonstrate that transmethylation inhibition by a novel reversible S-adenosyl-L-homocysteine hydrolase inhibitor leads to immunosuppression by reducing phosphorylation of several key proteins involved in TCR signaling, including Akt, Erk1/2, and NF-B. Remarkably, this effect was largely restricted to CD4 T cells and correlated with reduced arginine methylation of Vav1, an essential guanine nucleotide exchange factor in T cell stimulation. Treatment with the transmethylation inhibitor averted, and even ameliorated, the CD4-mediated autoimmune disease, experimental autoimmune encephalomyelitis. The data suggest that transmethylation is required for CD4 T cell activation, and its inhibition may be a novel approach in the treatment of multiple sclerosis, and other CD4-mediated autoimmune diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Brian R. Lawson at the current address: The Scripps Research Institute, Department of Immunology, IMM-3, 10550 North Torrey Pines Road, La Jolla CA 92037. E-mail address: blawson{at}scripps.edu

² Abbreviations used in this paper: SAH, S-adenosyl-L-homocysteine; SAHase, S-adenosyl-L-homocysteine hydrolase; DZ2002, methyl 4-(adenin-9-yl)-2-hydroxybutanoate; EAE, experimental autoimmune encephalomyelitis; PLP, proteolipid protein; MOG, myelin oligodendrocyte glycoprotein; shRNA, short hairpin RNA; PTX, pertussis toxin; DMA, mono and dimethyl arginine.

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