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

Linda Wooldridge, Mathew Clement, Anna 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 journalArticleResearchpeer-review

19 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 ∼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)3357-3366
Number of pages10
JournalJournal of Immunology
Volume184
Issue number7
DOIs
Publication statusPublished - 1 Apr 2010
Externally publishedYes

Cite this