CTLA-4 {middle dot} FasL Induces Early Apoptosis of Activated T Cells by Interfering with Anti-Apoptotic Signals

• Published in: The Journal of immunology (1950) Vol. 179; no. 11; pp. 7287 - 7294
• Main Authors: Orbach, Ariel, Rachmilewitz, Jacob, Parnas, Miram, Huang, Jui-Han, Tykocinski, Mark L, Dranitzki-Elhalel, Michael
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.12.2007
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; Animals; Antigens, CD - drug effects; Antigens, CD - immunology; Antigens, Differentiation - drug effects; Antigens, Differentiation - immunology; Apoptosis - immunology; CASP8 and FADD-Like Apoptosis Regulating Protein - immunology; Cell Cycle - immunology; Cell Proliferation - drug effects; Cells, Cultured; CTLA-4 Antigen; Fas Ligand Protein - antagonists & inhibitors; Fas Ligand Protein - immunology; Female; Mice; Mice, Inbred C57BL; Recombinant Fusion Proteins - antagonists & inhibitors; Recombinant Fusion Proteins - immunology; Signal Transduction - immunology; T-Lymphocytes - immunology; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.179.11.7287

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.