Dendritic cells (DC) activated by CpG DNA ex vivo are potent inducers of host resistance to an intracellular pathogen that is independent of IL-12 derived from the immunizing DC.
We used the model of murine leishmaniasis to evaluate the signals enabling Ag-pulsed dendritic cells (DC) to prime a protective Th1 response in vivo. Bone marrow-derived DC (BMDC) that had been activated by TNF-alpha or CD40 ligation were not able to induce protection against leishmaniasis in susceptible BALB/c mice. In contrast, all mice vaccinated with a single dose of Leishmania major Ag-pulsed BMDC stimulated by prior in vitro exposure to CpG-containing oligodeoxynucleotides (ODN) were completely protected, had a dramatic reduction in parasite burden, and developed an Ag-specific Th1 response. Importantly, systemic administration of CpG ODN was not required. Protection mediated by ex vivo CpG ODN-activated and Ag-pulsed DC was solid, as documented by resistance to reinfection with a higher parasite dose, and long-lasting, as immunized mice were still protected against L. major challenge 16 wk after vaccination. A significantly increased level of protection could also be elicited in resistant C57BL/6 mice. Surprisingly, IL-12 expression by the immunizing BMDC was not required for induction of host resistance. In contrast, the availability of IL-12 derived from recipient cells was essential for the initial triggering of protective immunity by transferred BMDC. Together, these findings demonstrate that the type of stimulatory signal is critical for activating the potential of DC to induce a Th1 response in vivo that confers complete protection against an intracellular pathogen. Moreover, they show that the impact of activated DC on the initiation of a protective Th cell response in vivo may be independent of their ability to produce IL-12.
Ramírez-Pineda
José R
JR
Institute for Molecular Biology of Infectious Diseases, University of Würzburg, Würzburg, Germany.
Fröhlich
Anja
A
Berberich
Christof
C
Moll
Heidrun
H
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000953:Antigens, Protozoan / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D019013:CD40 Antigens / Q000276:immunology; D018899:CpG Islands / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology / Q000637:transplantation*; D005260:Female; D007110:Immunity, Active; D007113:Immunity, Innate / Q000235:genetics; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D018664:Interleukin-12 / Q000096:biosynthesis / Q000502:physiology*; D007424:Intracellular Fluid / Q000276:immunology* / Q000469:parasitology; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology*; D016052:Protozoan Vaccines / Q000008:administration & dosage; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000953:Antigens, Protozoan; D019013:CD40 Antigens; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D016052:Protozoan Vaccines; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12