MHC class I molecules with Superenhanced CD8 binding properties bypass the requirement for cognate TCR recognition and nonspecifically activate CTLs

Linda Wooldridge, Mathew Clement, Anya Lissina, Emily S J Edwards, Kristin Ladell, Julia Ekeruche, Rachel E Hewitt, Bruno Laugel, Emma Gostick, David K Cole, Reno Debets, Cor Berrevoets, John J Miles, Scott R Burrows, David A Price, Andrew K Sewell

Research output: Contribution to journalArticle (Academic Journal)peer-review

24 Citations (Scopus)

Abstract

CD8(+) CTLs are essential for effective immune defense against intracellular microbes and neoplasia. CTLs recognize short peptide fragments presented in association with MHC class I (MHCI) molecules on the surface of infected or dysregulated cells. Ag recognition involves the binding of both TCR and CD8 coreceptor to a single ligand (peptide MHCI [pMHCI]). The TCR/pMHCI interaction confers Ag specificity, whereas the pMHCI/CD8 interaction mediates enhanced sensitivity to Ag. Striking biophysical differences exist between the TCR/pMHCI and pMHCI/CD8 interactions; indeed, the pMHCI/CD8 interaction can be >100-fold weaker than the cognate TCR/pMHCI interaction. In this study, we show that increasing the strength of the pMHCI/CD8 interaction by approximately 15-fold results in nonspecific, cognate Ag-independent pMHCI tetramer binding at the cell surface. Furthermore, pMHCI molecules with superenhanced affinity for CD8 activate CTLs in the absence of a specific TCR/pMHCI interaction to elicit a full range of effector functions, including cytokine/chemokine release, degranulation and proliferation. Thus, the low solution binding affinity of the pMHCI/CD8 interaction is essential for the maintenance of CTL Ag specificity.

Original languageEnglish
Pages (from-to)3357-66
Number of pages10
JournalJournal of Immunology
Volume184
Issue number7
DOIs
Publication statusPublished - 1 Apr 2010

Keywords

  • Antigen Presentation
  • Antigens, CD8
  • CD8-Positive T-Lymphocytes
  • Cell Separation
  • Cells, Cultured
  • Cytotoxicity, Immunologic
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Histocompatibility Antigens Class I
  • Humans
  • Lymphocyte Activation
  • Receptors, Antigen, T-Cell
  • T-Lymphocytes, Cytotoxic

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