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J. Biol. Chem., Vol. 281, Issue 37, 27190-27196, September 15, 2006

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Mast Cell Costimulation by CD226/CD112 (DNAM-1/Nectin-2)

A NOVEL INTERFACE IN THE ALLERGIC PROCESS^*

Ido Bachelet, Ariel Munitz, David Mankutad, and Francesca Levi-Schaffer, Affiliated with the David R. Bloom Center of Pharmacy at the Hebrew University of Jerusalem¹

From the Deparment of Pharmacology, The School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem and the Department of Obstetrics and Gynecology, Hadassah University Hospital, Jerusalem 91120, Israel

Mast cells have critical effector functions in various immune reactions. In allergic inflammation, mast cells interact with tissue-infiltrating eosinophils, forming a regulatory unit in the late and chronic phases of the allergic process. However, the pathways and molecules within this unit are still largely undefined. Here, we show that human mast cells and eosinophils express DNAX accessory molecule 1 (DNAM-1, CD226) and its ligand Nectin-2 (CD112). CD226 synergizes with FcRI on mast cells, and its engagement augments degranulation through a pathway involving Fyn, linker of activation of T-cells, phospholipase C 2, and CD18. This pathway is subject to negative interference by inhibitory receptors and is completely inhibited by linking IgE with IRp60 (CD300a) using a bispecific antibody. Moreover, blocking CD112 expressed on eosinophils using neutralizing antibodies normalized the hyperactivity resulting from IgE-dependent activation of mast cells co-cultured with eosinophils. Our findings demonstrate a novel interface between these two effector cells, implicating relevance for in vivo allergic states. Moreover, costimulatory responses might be a critical component in allergic reactions and may therefore become novel targets for anti-allergic therapy.

Received for publication, March 13, 2006 , and in revised form, June 13, 2006.

^* This work was supported by grants from the Aimwell Charitable Trust (UK), the Israeli Science Foundation (Israel) and a grant from the Italian Ministry of Foreign Affairs for joint research with Israel (Italy). 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 To whom correspondence should be addressed. Tel.: 972-2-6757512; Fax: 972-2-6758144; E-mail: fls{at}cc.huji.ac.il.

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