Different T cell receptor affinity thresholds and CD8 coreceptor dependence govern cytotxic T lymphocyte activation and tetramer properties

Laugel, Bruno Frederic, Berg, Hugo A. van den, Gostick, Emma, Cole, David ORCID: https://orcid.org/0000-0003-0028-9396, Wooldridge, Linda, Boulter, Jonathan M, Milicic, Anita, Price, David ORCID: https://orcid.org/0000-0001-9416-2737 and Sewell, Andrew ORCID: https://orcid.org/0000-0003-3194-3135 2007. Different T cell receptor affinity thresholds and CD8 coreceptor dependence govern cytotxic T lymphocyte activation and tetramer properties. The Journal of Biological Chemistry 282 (33) , pp. 23799-22810. 10.1074/jbc.M700976200

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Abstract

T cells have evolved a unique system of ligand recognition involving an antigen T cell receptor (TCR) and a coreceptor that integrate stimuli provided by the engagement of peptide-major histocompatibility complex (pMHC) antigens. Here, we use altered pMHC class I (pMHCI) molecules with impaired CD8 binding (CD8-null) to quantify the contribution of coreceptor extracellular binding to (i) the engagement of soluble tetrameric pMHCI molecules, (ii) the kinetics of TCR/pMHCI interactions on live cytotoxic T lymphocytes (CTLs), and (iii) the activation of CTLs by cell-surface antigenic determinants. Our data indicate that the CD8 coreceptor substantially enhances binding efficiency at suboptimal TCR/pMHCI affinities through effects on both association and dissociation rates. Interestingly, coreceptor requirements for efficient tetramer labeling of CTLs or for CTL activation by determinants displayed on the cell surface operated in different TCR/pMHCI affinity ranges. Wild-type and CD8-null pMHCI tetramers required monomeric affinities for cognate TCRs of KD < approximately 80 microM and approximately 35 microM, respectively, to label human CTLs at 37 degrees C. In contrast, activation by cellular pMHCI molecules was strictly dependent on CD8 binding only for TCR/pMHCI interactions with KD values >200 microM. Altogether, our data provide information on the binding interplay between CD8 and the TCR and support a model of CTL activation in which the extent of coreceptor dependence is inversely correlated to TCR/pMHCI affinity. In addition, the results reported here define the range of TCR/pMHCI affinities required for the detection of antigen-specific CTLs by flow cytometry.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Additional Information:	This research was originally published in the Journal of Biological Chemistry. Laugel B.F., Berg H.A., Gostick E., Cole D., Wooldridge L., Boulter J.M., Milicic A., Price D. and Sewell A. Different T cell receptor affinity thresholds and CD8 coreceptor dependence govern cytotxic T lymphocyte activation and tetramer properties. J. Biol. Chem. 2007; 282:23799-22810. © the American Society for Biochemistry and Molecular Biology or © the Author(s).
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	1083-351X
Date of First Compliant Deposit:	20 March 2018
Last Modified:	01 Nov 2023 07:39
URI:	https://orca.cardiff.ac.uk/id/eprint/292

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