N-glycosylation Bidirectionally Extends the Boundaries of Thymocyte Positive Selection by Decoupling Lck From Ca²⁺ Signaling

Nat Immunol. 2014 Nov;15(11):1038-45. doi: 10.1038/ni.3007. Epub 2014 Sep 28.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acyltransferases / genetics
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Calcium / metabolism
  • Calcium Signaling / immunology*
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Glycosylation
  • Lymphocyte Activation / immunology
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / immunology*
  • Major Histocompatibility Complex / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • N-Acetylglucosaminyltransferases / genetics
  • Polysaccharides / chemistry*
  • Receptors, Antigen, T-Cell / immunology*
  • Thymocytes / immunology*

Substances

  • Polysaccharides
  • Receptors, Antigen, T-Cell
  • Acyltransferases
  • MGAT1 protein, mouse
  • N-Acetylglucosaminyltransferases
  • alpha-1,6-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase
  • alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Calcium