title: Developmentally regulated glycosylation of the CD8alphabeta coreceptor stalk modulates ligand binding.
abstract: The functional consequences of glycan structural changes associated with cellular differentiation are ill defined. Herein, we investigate the role of glycan adducts to the O-glycosylated polypeptide stalk tethering the CD8alphabeta coreceptor to the thymocyte surface. We show that immature CD4(+)CD8(+) double-positive thymocytes bind MHCI tetramers more avidly than mature CD8 single-positive thymocytes, and that this differential binding is governed by developmentally programmed O-glycan modification controlled by the ST3Gal-I sialyltransferase. ST3Gal-I induction and attendant core 1 sialic acid addition to CD8beta on mature thymocytes decreases CD8alphabeta-MHCI avidity by altering CD8alphabeta domain-domain association and/or orientation. Hence, glycans on the CD8beta stalk appear to modulate the ability of the distal binding surface of the dimeric CD8 globular head domains to clamp MHCI.
authors.affiliation: Laboratory of Immunobiology, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Moody
authors.forename: D
authors.initials: D
authors.lastname: Chui
authors.forename: P A
authors.initials: PA
authors.lastname: Reche
authors.forename: J J
authors.initials: JJ
authors.lastname: Priatel
authors.forename: J D
authors.initials: JD
authors.lastname: Marth
authors.forename: E L
authors.initials: EL
authors.lastname: Reinherz
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D017637:Clonal Deletion / Q000502:physiology; D004268:DNA-Binding Proteins; D019281:Dimerization; D015329:Gene Rearrangement, T-Lymphocyte; D006031:Glycosylation; D006183:H-2 Antigens / Q000737:chemistry / Q000276:immunology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D011134:Polysaccharides / Q000737:chemistry / Q000502:physiology; D011485:Protein Binding; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012799:Sialyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000166:cytology*; D019076:Transgenes; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
chemical_list: D016827:CD8 Antigens; C433839:CD8alphabeta antigen; D004268:DNA-Binding Proteins; D006183:H-2 Antigens; D008024:Ligands; D011134:Polysaccharides; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; C064655:V(D)J recombination activating protein 2; D012799:Sialyltransferases; D019158:N-Acetylneuraminic Acid; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase