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J. Biol. Chem., Vol. 278, Issue 44, 43818-43830, October 31, 2003

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Targeted Deletion of CD44v7 Exon Leads to Decreased Endothelial Cell Injury but Not Tumor Cell Killing Mediated by Interleukin-2-activated Cytolytic Lymphocytes^*

Robert J. McKallip, Michael Fisher, Yoonkyung Do, Andras K. Szakal¶, Ursula Gunthert||, Prakash S. Nagarkatti, and Mitzi Nagarkatti**

From the Departments of Microbiology and Immunology, Pharmacology and Toxicology, and ^¶Anatomy, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298 and the ^||Institute for Medical Microbiology, University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland

In the current study, we investigated the nature and role of CD44 variant isoforms involved in endothelial cell (EC) injury and tumor cell cytotoxicity mediated by IL-2-activated killer (LAK) cells. Treatment of CD44 wild-type lymphocytes with IL-2 led to increased gene expression of CD44 v6 and v7 variant isoforms and to significant induction of vascular leak syndrome (VLS). CD44v6-v7 knockout (KO) and CD44v7 KO mice showed markedly reduced levels of IL-2-induced VLS. The decreased VLS in CD44v6-v7 KO and CD44v7 KO mice did not result from differential activation and expansion of CD8⁺ T cells, NK, and NK-T cells or from altered degree of perivascular lymphocytic infiltration in the lungs. LAK cells from CD44v7 KO mice showed a significant decrease in their ability to adhere to and mediate lysis of EC but not lysis of P815 tumor cells in vitro. CD44v7-mediated lysis of EC by LAK cells was dependent on the activity of phosphatidylinositol 3-kinase and tyrosine kinases. Interestingly, IL-2-activated LAK cells expressing CD44^hi but not CD44^lo were responsible for EC lysis. Furthermore, lysis of EC targets could be blocked by addition of soluble or enzymatic cleavage of CD44v6-v7-binding glycosaminoglycans. Finally, anti-CD44v7 mAbs caused a significant reduction in the adherence to and killing of EC and led to suppression of IL-2-induced VLS. Together, this study suggests that the expression of CD44v7 on LAK cells plays a specific role in EC injury and that it may be possible to reduce EC injury but not tumor cell killing by specifically targeting CD44v7.

Received for publication, April 29, 2003 , and in revised form, July 14, 2003.

^* This work was supported in part by National Institutes of Health Grants RO1 AI 053703, RO1 DA 016545, R21 DA 014885, RO1 HL 058641, F32 HL 10455, F32 ES 011732, and RO1 ES 09098, as well as by American Cancer Society Grant IRG-100036. Flow cytometry was supported in part by National Institutes of Health Grant P30 CA 16059. 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.

^** To whom correspondence and reprint requests should be addressed: Dept. of Microbiology and Immunology and Massey Cancer Center, Medical College of Virginia Campus, Virginia Commonwealth University, Box 980678, Richmond, VA 23298-0678. Tel.: 804-827-1555; Fax: 804-828-0676; E-mail: mnagark{at}hsc.vcu.edu.

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