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

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Abstract

CD8⁺ cytotoxic T lymphocytes (CTL) are essential for effective immune defence against intracellular microbes and neoplasia. CTL recognize short peptide fragments presented in association with major histocompatibility complex class I (MHCI) molecules on the surface of infected or dysregulated cells. Antigen recognition involves the binding of both T cell receptor (TCR) and CD8 co-receptor to a single ligand (pMHCI). The TCR/pMHCI interaction confers antigen specificity, whereas the pMHCI/CD8 interaction mediates enhanced sensitivity to antigen. 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. Here, we show that increasing the strength of the pMHCI/CD8 interaction by ~15-fold results in non-specific, cognate antigen-independent pMHCI tetramer binding at the cell surface. Furthermore, pMHCI molecules with super-enhanced affinity for CD8 activate CTL 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 antigen specificity.

Item ID:	45359
Item Type:	Article (Research - C1)
ISSN:	1550-6606
Funders:	Wellcome Trust (WT), Cardiff University (CU), Medical Research Council (MRC), Leverhulme Trust (LT), National Health and Medical Research Council (NHMRC)
Date Deposited:	05 Sep 2016 05:16
FoR Codes:	11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes:	92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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