Misfolding of MHC class I molecules in activated T cells allows cis-interactions with receptors and signalling molecules and is associated with tyrosine phosphorylation.

S.G Santos, Simon John Powis, F.A Arosa

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)

Abstract

Knowledge of the origin and biochemical status of beta(2)-microglobulin-free or misfolded major histocompatibility complex (MHC)-I molecules is essential for understanding their pleiotropic properties. Here we show that in normal human T cells, misfolding of MHC-I molecules is turned on upon activation and cell division and is proportional to the level of proliferation. Immunoprecipitation showed that a number of proteins are associated with MHC-I heavy chains at the surface of activated T cells, including the CD8alphabeta receptor and the chaperone tandem calreticulin/ERp57, associations that rely upon the existence of a pool of HC-10-reactive molecules. Biochemical analysis showed that misfolded MHC-I molecules present at the cell surface are fully glycosylated mature molecules. Importantly, misfolded MHC-I molecules are tyrosine phosphorylated and are associated with kinase activity. In vitro kinase assays followed by reprecipitation indicated that tyrosine phosphorylation of the class I heavy chain is probably mediated by a Src tyrosine kinase because Lck was found associated with HC-10 immunocomplexes. Finally, we show that inhibition of tyrosine phosphorylation by using the Src-family tyrosine kinase inhibitor PP2 resulted in enhanced release of MHC-I heavy chains from the cell surface of activated T cells and a slight down-regulation of cell surface W6/32-reactive molecules. This study provides new insights into the biology of MHC-I molecules and suggests that tyrosine phosphorylation may be involved in the regulation of MHC-I misfolding and expression.

Original languageEnglish
Pages (from-to)53062-53070
Number of pages9
JournalJournal of Biological Chemistry
Volume279
DOIs
Publication statusPublished - 17 Dec 2004

Keywords

  • MHC CLASS-I
  • HEAVY-CHAINS
  • MONOCLONAL-ANTIBODY
  • CYTOPLASMIC DOMAIN
  • ALPHA-3 DOMAIN
  • HLA MOLECULES
  • SURFACE
  • LYMPHOCYTES
  • ANTIGEN
  • HLA-B27

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