CTLA-4·FasL induces early apoptosis of activated T cells by interfering with anti-apoptotic signals

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

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 p27kip 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.

Original languageAmerican English
Pages (from-to)7287-7294
Number of pages8
JournalJournal of Immunology
Volume179
Issue number11
DOIs
StatePublished - 1 Dec 2007
Externally publishedYes

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