The Journal of Experimental Medicine
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Published online May 7, 2007
doi:10.1084/jem.20062342
The Journal of Experimental Medicine, Vol. 204, No. 5, 1131-1144
The Rockefeller University Press, 0022-1007 $30.00
© 2007 McCarthy et al.
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ARTICLE

 The length of lipids bound to human CD1d molecules modulates the affinity of NKT cell TCR and the threshold of NKT cell activation

Corinna McCarthy1, Dawn Shepherd1, Sebastian Fleire4, Victoria S. Stronge1, Michael Koch2, Petr A. Illarionov5, Giovanna Bossi3, Mariolina Salio1, Galit Denkberg6, Faye Reddington5, Andrea Tarlton1, B. Gopal Reddy7, Richard R. Schmidt7, Yoram Reiter6, Gillian M. Griffiths3, P. Anton van der Merwe3, Gurdyal S. Besra5, E. Yvonne Jones2, Facundo D. Batista4, and Vincenzo Cerundolo1

1 Tumour Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, 2 Cancer Research UK Receptor Structure Research Group, Division of Structural Biology, Wellcome Trust Centre for Human Genetics, and 3 Sir William Dunn School of Pathology, University of Oxford, Oxford OX3 9DS, UK
4 Lymphocyte Interaction Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, UK
5 School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
6 Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel
7 Fachbereich Chemie, Universitaet Konstanz, D-78457 Konstanz, Germany

CORRESPONDENCE Vincenzo Cerundolo: vincenzo.cerundolo{at}imm.ox.ac.uk

CD1d-restricted lymphocytes recognize a broad lipid range. However, how CD1d-restricted lymphocytes translate T cell receptor (TCR) recognition of lipids with similar group heads into distinct biological responses remains unclear. Using a soluble invariant NKT (iNKT) TCR and a newly engineered antibody specific for {alpha}-galactosylceramide ({alpha}-GalCer)–human CD1d (hCD1d) complexes, we measured the affinity of binding of iNKT TCR to hCD1d molecules loaded with a panel of {alpha}-GalCer analogues and assessed the rate of dissociation of {alpha}-GalCer and {alpha}-GalCer analogues from hCD1d molecules. We extended this analysis by studying iNKT cell synapse formation and iNKT cell activation by the same panel of {alpha}-GalCer analogues. Our results indicate the unique role of the lipid chain occupying the hCD1d F' channel in modulating TCR binding affinity to hCD1d–lipid complexes, the formation of stable immunological synapse, and cell activation. These data are consistent with previously described conformational changes between empty and loaded hCD1d molecules (Koch, M., V.S. Stronge, D. Shepherd, S.D. Gadola, B. Mathew, G. Ritter, A.R. Fersht, G.S. Besra, R.R. Schmidt, E.Y. Jones, and V. Cerundolo. 2005. Nat. Immunol 6:819–826), suggesting that incomplete occupation of the hCD1d F' channel results in conformational differences at the TCR recognition surface. This indirect effect provides a general mechanism by which lipid-specific lymphocytes are capable of recognizing both the group head and the length of lipid antigens, ensuring greater specificity of antigen recognition.

Abbreviations used: {alpha}-GalCer, {alpha}-galactosylceramide; cSMAC, central SMAC; GPI, glycosyl-phosphatidylinositol; GSL, glycosphingolipid; hCD1d, human CD1d; iNKT, invariant NKT; IRM, interference reflection microscopy; SMAC, supramolecular activation cluster; SPR, surface plasmon resonance.

C. McCarthy, D. Shepherd, and S. Fleire contributed equally to this paper.


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