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 without causing inflammation. Processing of phagocytosed apoptotic cells yields Ags that access the cytosol and the MHC class I pathway of engulfing cells and are recognized by Ag-specific CTL. We show here that injection of apoptotic RMA cells, a syngeneic T cell lymphoma, into C57BL/6 mice results in priming of a functional and long-lasting tumor-specific immune response. Cross-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-1beta cytokines, and is enhanced in IL-10 knockout mice. Moreover, immunization with dendritic cells (DCs), but not macrophages (Mphi), pulsed with apoptotic cells primes tumor-specific CTLs and confers protection against a tumor challenge. Our findings demonstrate that tumor cells undergoing apoptosis are, though scarcely, immunogenic in vivo, outline the different roles of Mphi and DCs in the physiologic clearance of unwanted cells, and have implications in designing immunomodulating vaccines.
Ronchetti
A
A
Laboratorio di Immunologia dei Tumori, Cancer Immunotherapy and Gene Therapy Program, Unità di Epidemiologia, Università Vita e Salute, Istituto Scientifico H San Raffaele, Milan, Italy.
Rovere
P
P
Iezzi
G
G
Galati
G
G
Heltai
S
S
Protti
M P
MP
Garancini
M P
MP
Manfredi
A A
AA
Rugarli
C
C
Bellone
M
M
D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002461:Cell Line, Transformed; D016207:Cytokines / Q000378:metabolism / Q000502:physiology*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D007274:Injections, Intraperitoneal; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D010586:Phagocytes / Q000276:immunology / Q000637:transplantation; D011925:Rauscher Virus; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D016207:Cytokines