title: N-acetylglucosaminyltransferase V (Mgat5)-mediated N-glycosylation negatively regulates Th1 cytokine production by T cells.
abstract: The differentiation of naive CD4(+) T cells into either proinflammatory Th1 or proallergic Th2 cells strongly influences autoimmunity, allergy, and tumor immune surveillance. We previously demonstrated that beta1,6GlcNAc-branched complex-type (N-acetylglucosaminyltransferase V (Mgat5)) N-glycans on TCR are bound to galectins, an interaction that reduces TCR signaling by opposing agonist-induced TCR clustering at the immune synapse. Mgat5(-/-) mice display late-onset spontaneous autoimmune disease and enhanced resistance to tumor progression and metastasis. In this study we examined the role of beta1,6GlcNAc N-glycan expression in Th1/Th2 cytokine production and differentiation. beta1,6GlcNAc N-glycan expression is enhanced by TCR stimulation independent of cell division and declines at the end of the stimulation cycle. Anti-CD3-activated splenocytes and naive T cells from Mgat5(-/-) mice produce more IFN-gamma and less IL-4 compared with wild-type cells, the latter resulting in the loss of IL-4-dependent down-regulation of IL-4Ralpha. Swainsonine, an inhibitor of Golgi alpha-mannosidase II, blocked beta1,6GlcNAc N-glycan expression and caused a similar increase in IFN-gamma production by T cells from humans and mice, but no additional enhancement in Mgat5(-/-) T cells. Mgat5 deficiency did not alter IFN-gamma/IL-4 production by polarized Th1 cells, but caused an approximately 10-fold increase in IFN-gamma production by polarized Th2 cells. These data indicate that negative regulation of TCR signaling by beta1,6GlcNAc N-glycans promotes development of Th2 over Th1 responses, enhances polarization of Th2 cells, and suggests a mechanism for the increased autoimmune disease susceptibility observed in Mgat5(-/-) mice.
authors.affiliation: Department of Antibacterials, Immunology, and Cancer, Pfizer Global Research and Development, Groton, CT 06340, USA.
authors.forename: Rodney
authors.initials: R
authors.lastname: Morgan
authors.forename: Guoyan
authors.initials: G
authors.lastname: Gao
authors.forename: Judy
authors.initials: J
authors.lastname: Pawling
authors.forename: James W
authors.initials: JW
authors.lastname: Dennis
authors.forename: Michael
authors.initials: M
authors.lastname: Demetriou
authors.forename: Baiyong
authors.initials: B
authors.lastname: Li
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006031:Glycosylation; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017351:N-Acetylglucosaminyltransferases / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism*; D011134:Polysaccharides / Q000096:biosynthesis / Q000378:metabolism; D018121:Receptors, Cytokine / Q000096:biosynthesis; D013154:Spleen / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D017026:Swainsonine / Q000494:pharmacology; D018417:Th1 Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism
chemical_list: D011134:Polysaccharides; D018121:Receptors, Cytokine; D015847:Interleukin-4; D007371:Interferon-gamma; D017351:N-Acetylglucosaminyltransferases; C052254:alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase; D017026:Swainsonine; D000117:Acetylglucosamine