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J. Biol. Chem., Vol. 283, Issue 49, 34414-34422, December 5, 2008

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Nanoscale Increases in CD2-CD48-mediated Intermembrane Spacing Decrease Adhesion and Reorganize the Immunological Synapse^*

Oren Milstein, Su-Yi Tseng, Toby Starr, Jaime Llodra^¶, Andrea Nans^¶, Mengling Liu^||, Martin K. Wild^**, P. Anton van der Merwe, David L. Stokes^¶, Yair Reisner, and Michael L. Dustin¹

From the Programs in Molecular Pathogenesis and ^¶Structural Biology, Helen and Martin Kimmel Center for Biology and Medicine of the Skirball Institute and New York University School of Medicine, New York, New York 10016, the ^||Division of Biostatistics, New York University Cancer Institute, New York, New York 10016, the Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel, the ^**Max Planck Institute of Molecular Medicine, 48149 Muenster, Germany, and the Sir William Dunn School of Pathology, Oxford University, South Parks Road, Oxford OX1 3RE, United Kingdom

The relationship between intermembrane spacing, adhesion efficiency, and lateral organization of adhesion receptors has not been established for any adhesion system. We have utilized the CD2 ligand CD48 with two (wild type CD48 (CD48-WT)), four (CD48-CD2), or five (CD48-CD22) Ig-like domains. CD48-WT was 10-fold more efficient in mediating adhesion than CD48-CD2 or CD48-CD22. Electron tomography of contact areas with planar bilayers demonstrated average intermembrane spacing of 12.8 nm with CD48-WT, 14.7 nm with CD48-CD2, and 15.6 nm with CD48-CD22. Both CD48-CD2 and CD48-CD22 chimeras segregated completely from CD48-WT in mixed contact areas. In contrast, CD48-CD2 and CD48-CD22 co-localized when mixed contacts were formed. Confocal imaging of immunological synapses formed between primary T lymphocytes and Chinese hamster ovary cells presenting major histocompatibility complex-peptide complexes, and different forms of CD48 demonstrated that CD48-CD2 and CD48-CD22 induce an eccentric CD2/T cell antigen receptor cluster. We propose that this reorganization of the immunological synapse sequesters the T cell antigen receptor in a location where it cannot interact with its ligand and dramatically reduces T cell sensitivity.

Received for publication, June 23, 2008 , and in revised form, August 28, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AI43542 (to M. L. D.), GM071044 (to D. L. S.), and P30 CA016087 (to M. L.). This work was also supported by European Molecular Biology Organization Fellowship ASTF.49.00-05 (to O. M.) and Leukemia and Lymphoma Society Fellowship 5456-04 (to S. Y. T.). 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 TIFF files containing the raw data for the representative three-dimensional data sets in Figs. 5 and 6. The files are are named based on the figure component and channel. These data can be inspected with image processing software, such as ImageJ (available on the World Wide Web).

¹ To whom correspondence should be addressed: Program in Molecular Pathogenesis, New York University School of Medicine, 540 1st Ave., New York, NY 10016. Tel.: 212-263-3207; Fax: 212-263-5711; E-mail: dustin{at}saturn.med.nyu.edu.

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