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An Essential Role for the Stalk Region of CD8β in the Coreceptor Function of CD8¹

Lorna Rettig^2,*, Louise McNeill^3,*, Nitza Sarner^*, Philippe Guillaume, Immanuel Luescher, Mauro Tolaini^*, Dimitris Kioussis^* and Rose Zamoyska^4,*

^* Molecular Immunology, Medical Research Council National Institute for Medical Research, London, United Kingdom and Ludwig Institute for Cancer Research, Lausanne Branch, Epalinges, Switzerland

The CD8β heterodimer is integral to the selection of the class I-restricted lineage in the thymus; however, the contribution of the CD8β chain to coreceptor function is poorly understood. To understand whether the CD8β membrane proximal stalk region played a role in coreceptor function, we substituted it with the corresponding sequence from the CD8 polypeptide and expressed the hybrid molecule in transgenic mice in place of endogenous CD8β. Although the stalk-swapped CD8β was expressed on the cell surface as a disulfide-bonded heterodimer at equivalent levels of expression to an endogenous CD8β molecule, it failed to restore selection of CD8⁺ class I MHC-restricted T cells and it altered the response of peripheral T cells. Thus, the stalk region of the CD8β polypeptide has an essential role in ensuring functionality of the CD8β heterodimer and its replacement compromises the interaction of CD8 with peptide-MHC complexes.

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 This work was supported by funding from the Medical Research Council U.K.

² Current address: UniversitätSpital Zürich, Onkologie Häldeliweg 4 8044 Zurich, CH, Switzerland.

³ Current address: Division of Rheumatology, University of Cambridge, Addenbrooke’s Hospital, Cambridge, U.K.

⁴ Address correspondence and reprint requests to Dr. Rose Zamoyska at the current address: Institute for Immunology and Infection Research, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT. E-mail address: Rose.Zamoyska{at}ed.ac.uk

⁵ Abbreviations used in this paper: DP, double positive; WT, wild type; RT, room temperature; FRET, förster resonance energy transfer; MFI, mean fluorescence intensity; SP, single positive; LN, lymph node; pMHC, peptide MHC.