HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 33, 23799-23810, August 17, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/33/23799    most recent M700976200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Laugel, B. Articles by Sewell, A. K. Search for Related Content PubMed PubMed Citation Articles by Laugel, B. Articles by Sewell, A. K. Social Bookmarking                      What's this?

Different T Cell Receptor Affinity Thresholds and CD8 Coreceptor Dependence Govern Cytotoxic T Lymphocyte Activation and Tetramer Binding Properties^*

Bruno Laugel¹, Hugo A. van den Berg, Emma Gostick, David K. Cole^¶, Linda Wooldridge^¶, Jonathan Boulter^¶, Anita Milicic, David A. Price, and Andrew K. Sewell^¶2

From the Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, United Kingdom, the Warwick Systems Biology Centre, University of Warwick, Coventry CU4 7AC, United Kingdom, and the ^¶Department of Medical Biochemistry and Immunology, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, United Kingdom

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 K_D < 80 µM and 35 µM, respectively, to label human CTLs at 37 °C. In contrast, activation by cellular pMHCI molecules was strictly dependent on CD8 binding only for TCR/pMHCI interactions with K_D values >200 µM. 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.

Received for publication, February 1, 2007 , and in revised form, April 23, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Ludwig Inst. for Cancer Research, Chemin des Boveresses 155, 1066 Epalinges, Switzerland.

² To whom correspondence should be addressed: Dept. of Medical Biochemistry and Immunology, Cardiff University School of Medicine, Henry Wellcome Bldg., Heath Park, South Parks Rd., Cardiff CF14 4XN, Wales, United Kingdom. Tel.: 44-2920-744-003; Fax: 44-2920-745-111; E-mail: sewellak{at}cardiff.ac.uk.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. S. Chervin, J. D. Stone, P. D. Holler, A. Bai, J. Chen, H. N. Eisen, and D. M. Kranz The Impact of TCR-Binding Properties and Antigen Presentation Format on T Cell Responsiveness J. Immunol., July 15, 2009; 183(2): 1166 - 1178. [Abstract] [Full Text] [PDF]