N-acetylglucosaminyltransferase V (Mgat5)-mediated N-glycosylation negatively regulates Th1 cytokine production by T cells

J Immunol. 2004 Dec 15;173(12):7200-8. doi: 10.4049/jimmunol.173.12.7200.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylglucosamine / metabolism
  • Animals
  • CD4-Positive T-Lymphocytes / enzymology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cells, Cultured
  • Down-Regulation / genetics
  • Down-Regulation / immunology*
  • Glycosylation
  • Humans
  • Interferon-gamma / antagonists & inhibitors*
  • Interferon-gamma / biosynthesis*
  • Interleukin-4 / biosynthesis
  • Lymphocyte Activation / genetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Transgenic
  • N-Acetylglucosaminyltransferases / biosynthesis
  • N-Acetylglucosaminyltransferases / deficiency
  • N-Acetylglucosaminyltransferases / metabolism*
  • Polysaccharides / biosynthesis
  • Polysaccharides / metabolism
  • Receptors, Cytokine / biosynthesis
  • Spleen / enzymology
  • Spleen / immunology
  • Spleen / metabolism
  • Swainsonine / pharmacology
  • Th1 Cells / drug effects
  • Th1 Cells / enzymology*
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Th2 Cells / enzymology
  • Th2 Cells / immunology
  • Th2 Cells / metabolism


  • Polysaccharides
  • Receptors, Cytokine
  • Interleukin-4
  • Interferon-gamma
  • N-Acetylglucosaminyltransferases
  • alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase
  • Swainsonine
  • Acetylglucosamine