Immunogenicity of apoptotic cells in vivo: Role of antigen load, antigen-presenting cells, and cytokines

Apoptosis allows the clearance of unwanted cells from living tissues withou t causing inflammation. Processing of phagocytosed apoptotic cells yields A gs that access the cytosol and the MHC class I pathway of engulfing cells a nd are recognized by Ag-specific CTL, We show here that injection of apopto tic RMA cells, a syngeneic T cell lymphoma, into C57BL/6 mice results in pr iming of a functional and long-lasting tumor-specific immune response. Cros s-priming of CTLs by apoptotic cells requires CD4(+) T cell help. Apoptotic cells, however, are at least 20-fold less immunogenic than nonreplicating live cells. Immunogenicity of apoptotic cells is proportional to the number of cells injected, correlates with the serum concentration of IL-10 and IL -1 beta cytokines, and is enhanced in IL-10 knockout mice, Moreover, immuni zation with dendritic cells (DCs), but not macrophages (M phi), pulsed with apoptotic cells primes tumor-specific CTLs and confers protection against a tumor challenge. Our findings demonstrate that tumor cells undergoing apo ptosis are, though scarcely, immunogenic in vivo, outline the different rol es of M phi and DCs in the physiologic clearance of unwanted cells, and hav e implications in designing immunomodulating vaccines.