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* Department of Antibacterials, Immunology, and Cancer, Pfizer Global Research and Development, Groton, CT 06340;
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada; and
Departments of Neurology and Microbiology and Molecular Genetics, University of California, Irvine, CA 92697
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 
1,6GlcNAc-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 1,6GlcNAc N-glycan expression in Th1/Th2 cytokine production and differentiation. 1,6GlcNAc 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-
and less IL-4 compared with wild-type cells, the latter resulting in the loss of IL-4-dependent down-regulation of IL-4R
. Swainsonine, an inhibitor of Golgi -mannosidase II, blocked 1,6GlcNAc N-glycan expression and caused a similar increase in IFN- production by T cells from humans and mice, but no additional enhancement in Mgat5–/– T cells. Mgat5 deficiency did not alter IFN-/IL-4 production by polarized Th1 cells, but caused an 
10-fold increase in IFN- production by polarized Th2 cells. These data indicate that negative regulation of TCR signaling by 1,6GlcNAc 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.
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