TY - JOUR
T1 - CTLA-4·FasL induces early apoptosis of activated T cells by interfering with anti-apoptotic signals
AU - Orbach, Ariel
AU - Rachmilewitz, Jacob
AU - Parnas, Miram
AU - Huang, Jui Han
AU - Tykocinski, Mark L.
AU - Dranitzki-Elhalel, Michael
PY - 2007/12/1
Y1 - 2007/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=38849092640&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.179.11.7287
DO - 10.4049/jimmunol.179.11.7287
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C2 - 18025171
AN - SCOPUS:38849092640
SN - 0022-1767
VL - 179
SP - 7287
EP - 7294
JO - Journal of Immunology
JF - Journal of Immunology
IS - 11
ER -