title: N-glycosylation bidirectionally extends the boundaries of thymocyte positive selection by decoupling Lck from Ca²⁺ signaling.
abstract: Positive selection of diverse yet self-tolerant thymocytes is vital to immunity and requires a limited degree of T cell antigen receptor (TCR) signaling in response to self peptide-major histocompatibility complexes (self peptide-MHCs). Affinity of newly generated TCR for peptide-MHC primarily sets the boundaries for positive selection. We report that N-glycan branching of TCR and the CD4 and CD8 coreceptors separately altered the upper and lower affinity boundaries from which interactions between peptide-MHC and TCR positively select T cells. During thymocyte development, N-glycan branching varied approximately 15-fold. N-glycan branching was required for positive selection and decoupled Lck signaling from TCR-driven Ca(2+) flux to simultaneously promote low-affinity peptide-MHC responses while inhibiting high-affinity ones. Therefore, N-glycan branching imposes a sliding scale on interactions between peptide-MHC and TCR that bidirectionally expands the affinity range for positive selection.
authors.affiliation: 1] Department of Neurology, University of California, Irvine, Irvine, California, USA. [2] Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, California, USA. [3] Institute for Immunology, University of California, Irvine, Irvine, California, USA.
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Zhou
authors.affiliation: 1] Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, California, USA. [2] Institute for Immunology, University of California, Irvine, Irvine, California, USA.
authors.forename: Haik
authors.initials: H
authors.lastname: Mkhikian
authors.affiliation: 1] Department of Neurology, University of California, Irvine, Irvine, California, USA. [2] Institute for Immunology, University of California, Irvine, Irvine, California, USA.
authors.forename: Ani
authors.initials: A
authors.lastname: Grigorian
authors.affiliation: Department of Neurology, University of California, Irvine, Irvine, California, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Hong
authors.affiliation: Department of Neurology, University of California, Irvine, Irvine, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Neurology, University of California, Irvine, Irvine, California, USA.
authors.forename: Araz
authors.initials: A
authors.lastname: Arakelyan
authors.affiliation: 1] Department of Neurology, University of California, Irvine, Irvine, California, USA. [2] Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, California, USA. [3] Institute for Immunology, University of California, Irvine, Irvine, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Demetriou
mesh_terms: D000217:Acyltransferases / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D006031:Glycosylation; D008213:Lymphocyte Activation / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D011134:Polysaccharides / Q000737:chemistry*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D060168:Thymocytes / Q000276:immunology*
chemical_list: D011134:Polysaccharides; D011948:Receptors, Antigen, T-Cell; D000217:Acyltransferases; C459903:MGAT1 protein, mouse; D017351:N-Acetylglucosaminyltransferases; C063313:alpha-1,6-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase; C052254:alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D002118:Calcium