The immunological potential of apoptotic debris produced by tumor cells and during HIV infection

Apoptosis is a major cause of cell death in health and disease. In contrast to necrosis, apoptosis does not induce an inflammatory response and the cellular debris produced by apoptosis has been assumed to be biologically inert. This review challenges this assumption by suggesting that apoptotic debris (especially in the context of growing tumors or during HIV infection) may have immunological activities, mainly immunosuppressive but perhaps also immunostimulatory. In many cases, the surface of apoptotic cells differs from normal cells in that phosphatidylserine (PS) is aberrantly exposed on the external face of the cell membrane. Liposomes composed of PS may down-modulate macrophage anti-leishmanial activities, suppress macrophage TNF production, suppress lymphocyte proliferation, and increase macrophage proliferation. "Membrane shedding" has been described in certain malignancies where apoptosis may be occurring, and the shed tumor membrane vesicles have been shown to reduce MHC class II expression on macrophages and decrease lymphocyte responsiveness, perhaps because of their ganglioside content. Finally, the apoptotic debris from HIV-infected cells may bear on its surface viral proteins which contain immunosuppressive peptide sequences. This debris may also use viral envelope proteins to fuse into macrophages and thereby avoid phagocytosis and lysosomal destruction. These considerations suggest that the flux of apoptosing cells and debris through the immune system that occurs during tumor growth and HIV infection should not be assumed to be immunologically neutral. In particular, HIV-related apoptosis may have immunosuppressive effects in addition to the numerical depletion of lymphocytes.