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

Wooldridge, Linda, Clement, Mathew, Lissina, Anna, Edwards, Emily, Ladell, Kristin Ingrid, Ekeruche, Julia, Hewitt, R. E., Laugel, Bruno Frederic, Gostick, Emma, Cole, David, Debets, R., Berrevoets, C., Miles, John James, Burrows, S. R., Price, David A. and Sewell, Andrew K. 2010. MHC Class I molecules with superenhanced CD8 binding properties bypass the requirement for cognate TCR recognition and nonspecifically activate CTLs. Journal of Immunology 184 (7) , pp. 3357-3366. 10.4049/jimmunol.0902398

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RZ Other systems of medicine
Publisher: American Association of Immunologists
ISSN: 0022-1767
Last Modified: 10 Oct 2017 14:08
URI: http://orca.cf.ac.uk/id/eprint/24882

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