Immunotherapy: Open Access
Open Access
ISSN: 2471-9552
ISSN: 2471-9552
Maryam Rashidi, Esther Bandala-Sanchez, Yuxia Zhang, Kate Lawler, John Wentworth, James Vince and Leonard C Harrison
Walter & Eliza Hall Institute of Medical Research, Australia
Posters & Accepted Abstracts: Immunother Open Acc
Background & Aim: CD52 is a glycosyl-phosphatidylinositol (GPl)-anchored cell surface glycopeptide but its physiological role has not been well defined. We recently showed that cell surface CD52 suppresses T-cell function. Following activation, T-cells release CD52, which inhibits T-cell receptor signaling in bystander T-cells. In the present study, we demonstrate that soluble CD52 can induce suppression of NF-�ºB activation and death in innate immune cells. Method & Results: Exposure of innate immune cells to low concentrations (10 �¼g per ml) of CD52-Fc potently inhibited NF-�ºB signaling and cytokine production in response to a range of inflammatory stimuli, including both TLR and TNFR ligands without evidence of cell death. However, at higher concentrations (30 �¼g/ml and above) we observed that CD52-Fc induced rapid (within 24 hours) cell death in human monocytes and mouse bone marrow-derived macrophages (BMDMs) and dendritic cells (BMDCs). Cell death was caspase-dependent because the pan-caspase inhibitor Q-VD-OPh inhibited CD52-Fc-induced cell death. In addition, high-dose CD52-Fc induced cleavage of caspases 8 and 9 and its ability to induce cell death was significantly decreased in caspase-8- deficient BMDMs. When cell death was inhibited by Q-VD-OPh, CD52-Fc still suppressed cytokine production, demonstrating that suppression of cytokine production by CD52-Fc is separable from and not due to its ability to cause cell death. Conclusion: Our findings demonstrate that, in addition to suppressing NF-�ºB signaling and cytokine production, soluble CD52-Fc induces cell death in myeloid cells through the extrinsic apoptotic pathway, suggesting that CD52-Fc may have therapeutic potential for the treatment of myeloproliferative disorders.
Email: rashidi@wehi.edu.au