Glycosylation, Immunity, and Autoimmunity

Lymphocyte activation events figure prominently in initiating the adaptive immune response (Dustin and Chan, 2000). Plant lectins like phytohemagglutinin have long been used as surrogates for authentic lymphocyte activational stimuli. These carbohydrate binding proteins activate lymphocytes by cross-linking many lymphocyte cell surface glycoproteins, including some that contribute to the immunological synapse (Dustin and Chan, 2000). Although it is difficult to attach physiological significance to plant lectin-dependent activation events, they have nonetheless suggested that protein-glycan interactions may contribute to immune system function. Glycans decorate the surfaces of all mammalian cells, and the extracellular matrix with which they interact. Their abundance and significant size (a typical N-glycan is approximately the length of one Ig domain; imply roles of consequence in cell-cell and cell-matrix interactions. In general, mammalian glycans are the product of a few glycohydrolases and dozens of glycosyltransferases acting sequentially in the secretory pathway. Each glycosyltransferase uses a single nucleotide sugar substrate, and forms a specific linkage between one monosaccharide and a glycan precursor. Each cell's glycosyltransferase repertoire thus dictates which glycan structures it will express, among a much larger number of possible structures. These substantial combinatorial possibilities for oligosaccharide structure provide enormous potential for information display. The job of decoding this information is assigned in part to the large number of mammalian carbohydrate binding proteins, including the galectins, a family of lectins with specificity for galactose-containing glycans. Efforts to convert the information "potential" inherent in glycan structure to something more tangible have been thwarted in part because determining glycan structure is technically challenging, and is made even more difficult by heterogeneity in protein glycosylation. Mammalian cell mutants with aberrant glycan phenotypes have been important in defining glycosylation loci, whereas insight into glycan function has been sought by manipulating glycosylation pathways in the animal. Recent efforts involving genetic manipulation of O- and N-glycosylation pathways in mice illuminate roles for cell surface glycans modulating extracellular molecular interactions with functional relevance to the immune system.