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CTLA-4 · FasL Induces Early Apoptosis of Activated T Cells by Interfering with Anti-Apoptotic Signals¹

Ariel Orbach^*, Jacob Rachmilewitz, Miram Parnas^*, Jui-Han Huang, Mark L. Tykocinski and Michael Dranitzki-Elhalel^2,*

^* Nephrology and Hypertension Services, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104

The fusion protein CTLA-4 · FasL, a paradigmatic "trans signal converter protein", can attach to APC surfaces and in effect convert B7-activating costimulator signals into inhibitory Fas receptor-generated signals. The present study investigates CTLA-4 · FasL’s mechanism of action. A combination of p27^kip and proliferating cell nuclear Ag Western blot and propidium iodide flow cytometric analysis showed no CTLA-4 · FasL effect on cell cycle entry and progression, pointing away from the kind of classical anergy associated with CTLA-4 · Ig. Significantly, CTLA-4 · FasL elicited apoptosis (as detected by annexin-V/propidium iodide costaining) as early as 24 h after T cell activation, suggesting that some coordinate signaling might be capacitating the Fas receptor. Significantly, CTLA-4 · FasL, but not CTLA-4 · Ig, anti-Fas mAb, or the two in combination, abrogated the usual increase in expression of the anti-apototic protein, cFLIP. Furthermore, activation of caspases 8 and 3 were not affected by CTLA-4 · FasL. These findings suggest a model for CTLA-4 · FasL action wherein there is coordinate triggering of a death receptor and suppression of a proapoptotic protein.

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 This work was supported by National Institutes of Health Grants AI31044-11 and CA74958 (to M.L.T.), and by the Israeli Society of Nephrology Research Fund for 2003 and 2005 (to M.D.E.).

² Address correspondence and reprint requests to Dr. Michal Dranitzki-Elhalel, Nephrology and Hypertension Services, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. E-mail address: michalelhalel{at}gmail.com

³ Abbreviations used in this paper: TSCP, trans signal converter proteins; PI, propidium iodide; PCNA, proliferating cell nuclear Ag; cFLIPs, cFLIP short.

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