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J. Biol. Chem., Vol. 283, Issue 35, 24254-24263, August 29, 2008

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Increased Mobility of Major Histocompatibility Complex I-Peptide Complexes Decreases the Sensitivity of Antigen Recognition^*

Jean-Manuel Segura, Philippe Guillaume, Silke Mark¹, Danijel Dojcinovic, Alexandre Johannsen, Giovanna Bosshard, Georgi Angelov, Daniel F. Legler^¶2, Horst Vogel, and Immanuel F. Luescher³

From the Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, CH-1066 Epalinges, Ecole Polytechnique Fédérale de Lausanne, Institut des Sciences et Ingénierie Chimiques, CH-1015 Lausanne, and ^¶Biotechnology Institute Thurgau, University of Konstanz, CH-8280 Kreuzlingen, Switzerland

CD8⁺ cytotoxic T lymphocytes (CTL) can recognize and kill target cells expressing only a few cognate major histocompatibility complex (MHC) I-peptide complexes. This high sensitivity requires efficient scanning of a vast number of highly diverse MHC I-peptide complexes by the T cell receptor in the contact site of transient conjugates formed mainly by nonspecific interactions of ICAM-1 and LFA-1. Tracking of single H-2K^d molecules loaded with fluorescent peptides on target cells and nascent conjugates with CTL showed dynamic transitions between states of free diffusion and immobility. The immobilizations were explained by association of MHC I-peptide complexes with ICAM-1 and strongly increased their local concentration in cell adhesion sites and hence their scanning by T cell receptor. In nascent immunological synapses cognate complexes became immobile, whereas noncognate ones diffused out again. Interfering with this mobility modulation-based concentration and sorting of MHC I-peptide complexes strongly impaired the sensitivity of antigen recognition by CTL, demonstrating that it constitutes a new basic aspect of antigen presentation by MHC I molecules.

Received for publication, May 8, 2008 , and in revised form, June 20, 2008.

^* This work was supported in part by Grant 310000-108251 from Swiss National Foundation (to I. F. L.) and internal Ecole Polytechnique Fédérale de Lausanne grants (to H. V.). 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 Methods, Figs. S1-S8, and Videos 1-6.

¹ Present address: Kuros Biosurgery AG, Technoparkstrasse 1, CH-8005 Zurich, Switzerland.

² Recipient of a career development award from the Prof. Dr. Max Cloëtta Foundation.

³ To whom correspondence should be addressed. Fax: 41 21 692 5995; E-mail: Immanuel.Luescher{at}licr.unil.ch.

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