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J. Biol. Chem., Vol. 280, Issue 30, 27491-27501, July 29, 2005

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Interaction between the CD8 Coreceptor and Major Histocompatibility Complex Class I Stabilizes T Cell Receptor-Antigen Complexes at the Cell Surface^*

Linda Wooldridge, Hugo A. van den Berg¶||, Meir Glick**, Emma Gostick, Bruno Laugel, Sarah L. Hutchinson, Anita Milicic, Jason M. Brenchley, Daniel C. Douek, David A. Price, and Andrew K. Sewell¶¶

From the T Cell Modulation Group, Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Road, Oxford OX1 3SY, United Kingdom, the ^¶Institute of Mathematics, Statistics and Actuarial Science, University of Kent, Canterbury CT2 7NF, United Kingdom, the ^**Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, and the Human Immunology Section, Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, Maryland 20892

The off-rate (k_off) of the T cell receptor (TCR)/peptide-major histocompatibility complex class I (pMHCI) interaction, and hence its half-life, is the principal kinetic feature that determines the biological outcome of TCR ligation. However, it is unclear whether the CD8 coreceptor, which binds pMHCI at a distinct site, influences this parameter. Although biophysical studies with soluble proteins show that TCR and CD8 do not bind cooperatively to pMHCI, accumulating evidence suggests that TCR associates with CD8 on the T cell surface. Here, we titrated and quantified the contribution of CD8 to TCR/pMHCI dissociation in membrane-constrained interactions using a panel of engineered pMHCI mutants that retain faithful TCR interactions but exhibit a spectrum of affinities for CD8 of >1,000-fold. Data modeling generates a "stabilization factor" that preferentially increases the predicted TCR triggering rate for low affinity pMHCI ligands, thereby suggesting an important role for CD8 in the phenomenon of T cell cross-reactivity.

Received for publication, January 18, 2005 , and in revised form, April 5, 2005.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data on the decay of pMHCI tetramers (Figs. S1 and S2) and on pMHCI/CD8 interaction (Fig. S3).

A Wellcome Trust Prize Student.

^|| A Wellcome Trust Research Training Fellow.

Medical Research Council (United Kingdom) Clinician Scientist.

^¶¶ A Wellcome Trust Senior Fellow and to whom correspondence should be addressed. Tel.: 44-1865-281539; Fax: 44-1865-281530; E-mail: andy.sewell{at}ndm.ox.ac.uk.

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