Inhibition of transmethylation down-regulates CD4 T cell activation and curtails development of autoimmunity in a model system.
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-kappaB. 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.
Lawson
Brian R
BR
Diazyme Laboratories Division, General Atomics, San Diego, CA 92186, USA. blawson@scripps.edu
Manenkova
Yulia
Y
Ahamed
Jasimuddin
J
Chen
Xiaoru
X
Zou
Jian-Ping
JP
Baccala
Roberto
R
Theofilopoulos
Argyrios N
AN
Yuan
Chong
C
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors*; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy*; D002087:Butyrates / Q000494:pharmacology / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D015536:Down-Regulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D008745:Methylation; D051379:Mice; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction
D002087:Butyrates; D004791:Enzyme Inhibitors; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496619:Vav1 protein, mouse; C509291:methyl 4-(adenin-9-yl)-2-hydroxybutanoate; D043383:Adenosylhomocysteinase; D000225:Adenine; D002118:Calcium