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

Wooldridge, Linda, Clement, Mathew ORCID: https://orcid.org/0000-0002-9280-5281, Lissina, Anna, Edwards, Emily ORCID: https://orcid.org/0000-0002-0240-4370, Ladell, Kristin Ingrid ORCID: https://orcid.org/0000-0002-9856-2938, Ekeruche, Julia, Hewitt, R. E., Laugel, Bruno Frederic, Gostick, Emma, Cole, David ORCID: https://orcid.org/0000-0003-0028-9396, Debets, R., Berrevoets, C., Miles, John James, Burrows, S. R., Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737 and Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135 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:	Schools > Medicine Research Institutes & Centres > 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:	27 Jul 2023 01:07
URI:	https://orca.cardiff.ac.uk/id/eprint/24882

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