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Published online before print May 3, 2004

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(Journal of Leukocyte Biology. 2004;76:116-124.)
© 2004 by Society for Leukocyte Biology

Cross-linking of MHC class I molecules on human NK cells inhibits NK cell function, segregates MHC I from the NK cell synapse, and induces intracellular phosphotyrosines

Gonzalo Rubio^*, Xavier Férez, María Sánchez-Campillo, Jesús Gálvez, Salvador Martí^*, Rocío Verdú^*, Trinidad Hernández-Caselles and Pilar García-Peñarrubia^,1

^* Division of Immunology, Miguel Hernández University, San Juan de Alicante, Spain;
Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, Murcia, Spain; and
Laboratory of Physical Chemistry, Faculty of Science, Murcia, Spain

¹Correspondence: Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, 30100 Espinardo, Murcia, Spain. E-mail: pigarcia{at}um.es

Engagement of major histocompatibility complex (MHC) class I molecules on immune cells, where they are usually highly expressed, induces signal transduction events of unclear significance. We show here that antibody-mediated cross-linking of MHC-I molecules on human natural killer (NK) cells inhibits their cytotoxic activity against tumor target cells. Inhibition by anti-MHC class I monoclonal antibody exhibits molecular specificity and is an isotype and Fc-independent process. Physical hindrance of specific molecular recognition, induction of apoptosis, or reciprocal NK cell killing, which could be induced by cross-linking of MHC I molecules, has also been ruled out as putative mechanisms of inhibition. Confocal microscopy analysis revealed that MHC class I molecules on the surface of NK cells colocalize constitutively with GM1, a marker of lipid rafts. Cross-linking of MHC class I resulted in the asymmetric redistribution of GM1-enriched raft domains, which are concentrated to the immunological synapse, and MHC I molecules, which segregate to the opposite pole. Also, the cross-linking of MHC I on NK cells induced intracellular tyrosine phosphorylations. These results suggest that MHC I molecules on NK cells could transmit inhibitory signals upon engagement with putative ligands expressed on the surface of those cells that need to be protected from natural cytotoxicity.

Key Words: rafts colocalization • cytotoxicity • E:T conjugation

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