Prolonged antigen storage endows merocytic dendritic cells with enhanced capacity to prime anti-tumor responses in tumor-bearing mice.
Tumor cell vaccination with irradiated autologous tumor cells is a promising approach to activate tumor-specific T cell responses without the need for tumor Ag identification. However, uptake of dying cells by dendritic cells (DCs) is generally a noninflammatory or tolerizing event to prevent the development of autoreactive immune responses. In this study, we describe the mechanisms that confer the potent T cell priming capacity of a recently identified a population of DCs (merocytic DCs [mcDCs]) that potently primes both CD8(+) and CD4(+) T cells to cell-associated Ags upon uptake of apoptotic cells. mcDCs acquired cell-associated materials through a process of merocytosis that is defined by the uptake of small particles that are stored in nonacidic compartments for prolonged periods, sustained Ag presentation, and the induction of type I IFN. T cells primed by mcDCs to cell-associated Ags exhibit increased primary expansion, enhanced effector function, and increased memory formation. By using transgenic T cell transfer models and endogenous models, we show that treatment of tumor-bearing mice with mcDCs that have been exposed to dying tumor cells results in tumor suppression and increased host survival through the activation of naive tumor-specific CD8(+) T cells as well as the reinvigoration of tumor-specific T cells that had been rendered nonresponsive by the tumor in vivo. The potent capacity of mcDCs to prime both CD4(+) and CD8(+) T cells to cell-associated Ags under immunosuppressive conditions makes this DC subset an attractive target for tumor therapies as well as interventional strategies for autoimmunity and transplantation.
Reboulet
Rachel A
RA
Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
Hennies
Cassandra M
CM
Garcia
Zacarias
Z
Nierkens
Stefan
S
Janssen
Edith M
EM
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism* / Q000502:physiology; D039481:CD11b Antigen / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D004306:Dose-Response Relationship, Immunologic; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data
D000951:Antigens, Neoplasm; D039481:CD11b Antigen