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

Abstract

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-α 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.

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

“…The CD8 + DC then become efficient stimulators of CD4 T cell proliferation and extremely efficient in inducing effector cells, as measured by high levels of IFN-c production. Our observation is in accordance with several studies showing that CpG-activated DC are potent inducers of immune responses against intracellular pathogens in vivo [41,42]. It is not clear why the effect of CpG is much more potent on CD8 + DC, since both CD8 + and CD8 -DC express TLR9 and up-regulate costimulatory molecules to the same extent ( [43] and data not shown).…”

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

“…As professional APCs and potential targets for Leishmania infection, DCs play multiple roles in leishmaniasis: updating/transporting parasites (Moll et al, 1995), initiating innate immunity (Schleicher et al, 2007), priming parasitespecific CD4 + and CD8 + T cells, and maintaining T cell memory/activity (Baldwin et al, 2004;Belkaid et al, 2002;Bertholet et al, 2005;Zaph et al, 2004). Recently, DC-based vaccination for the control of L. major-induced cutaneous leishmaniasis has gained special attention (Ramirez-Pineda et al, 2004;Remer et al, 2007). However, studies from our and other groups have revealed marked differences in DC responsiveness to Old World versus New World Leishmania parasites.…”

Co‐operative action of interleukin‐10 and interferon‐γ to regulate dendritic cell functions

“…[15][16][17][18][19][20] However, no report has demonstrated the co-operative action of IL-10 and IFN-c on DC functions. We examined the effect of IL-10 combined with IFN-c on DC functions using murine bone marrow-derived conventional DCs.…”