The Immune Response Modifier and Toll-Like Receptor 7 Agonist S-27609 Selectively Induces IL-12 and TNF-α Production in CD11c+CD11b+CD8− Dendritic Cells

Doxsee, Christie L.; Riter, Tony R.; Reiter, Michael J.; Gibson, Shelia J.; Vasilakos, John P.; Kedl, Ross M.

doi:10.4049/jimmunol.171.3.1156

Cited by 95 publications

(96 citation statements)

References 70 publications

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“…Subset-specific up-regulation of costimulatory molecules has been observed in other in vivo models, including after administration of ␣-galactoceramide or TLR ligands and during infection with certain parasites or viruses (11, 23, 25, 35-37). The differential capacities of DC subsets to up-regulate CD80, CD86, or CD40 in response to microbial infection could be due to differential expression of TLRs (5,38,39). However, TLR-deficient DC up-regulate costimulatory molecules as well as TLR-expressing DC in mixed bone marrow chimeras after administration of the TLR agonist (22).…”

Section: Discussionmentioning

confidence: 99%

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TNF-α-Dependent and -Independent Maturation of Dendritic Cells and Recruited CD11cintCD11b+ Cells during Oral Salmonella Infection

Sundquist

Wick

2005

The Journal of Immunology

114

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Maturation of dendritic cells (DC) is crucial for their ability to induce adaptive immunity. Although several mediators of DC maturation have been found, their contributions to DC maturation during infection are poorly understood. In this study we show that murine conventional (CD11chigh) DC up-regulate costimulatory molecules in a subset-specific manner after oral Salmonella infection. Although both CD8α+ and CD8α− subsets increase CD86 expression, CD40 was preferentially up-regulated on CD8α+ DC, and CD80 was preferentially increased on CD8α− DC. In addition, high levels of CD80 and CD86 were found on CD11cintCD11b+ cells that accumulated in infected organs. Costimulatory molecules were simultaneously induced on CD11chigh and CD11cintCD11b+ cells in Peyer’s patches, mesenteric lymph nodes and spleen 5 days after infection despite different kinetics of peak bacterial burden in these organs. Up-regulation of costimulatory molecules occurred on all DC within the respective subset. Moreover, <1% of CD11c-expressing cells associated with Salmonella expressing enhanced GFP in vivo. Thus, DC maturation did not depend on bacterial uptake. Rather, infection-induced up-regulation of CD80, CD86, and CD40 on CD11c-expressing cells of mesenteric lymph nodes was dependent on TNFR type I (TNFRI) signaling. Although indirect up-regulation of costimulatory molecules on DC and CD11cintCD11b+ cells was TNFRI dependent, cells directly associated with Salmonella were able to mature independently of TNFRI signaling. Thus, Salmonella-induced TNF-α is an important mediator of indirect DC maturation during infection, whereas a TNF-α-independent maturation pathway contributes to direct maturation of bacteria-associated DC.

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Section: Discussionmentioning

confidence: 99%

“…Ϫ DC (23,38) despite differential TLR7 expression on these subsets detected at the mRNA level (38,39). Thus, the subset-specific up-regulation of costimulatory molecules could be dependent on a differential capacity of DC subsets to respond to proinflammatory cytokines (11), rather than a differential expression of TLRs.…”

Section: Discussionmentioning

confidence: 99%

TNF-α-Dependent and -Independent Maturation of Dendritic Cells and Recruited CD11cintCD11b+ Cells during Oral Salmonella Infection

Sundquist

Wick

2005

The Journal of Immunology

114

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“…Recent studies demonstrated that the activation of NK cells by DC can provide an early source of IFN-␥ that is necessary for T H 1 responses (31). Similarly, the activation of innate immune response cells via TLR signaling can also provide help, in the form of inflammatory cytokines and DC activation, for Ag-specific T cell responses (26,28,(32)(33)(34)(35). Such activation of innate immune signaling may help overcome immune tolerance to self Ags (28,36,37) or disrupt regulatory T cell effects (38).…”

Section: Discussionmentioning

confidence: 99%

NK and CD4 Cells Collaborate to Protect against Melanoma Tumor Formation in the Brain

Prins¹,

Khan-Farooqi³

et al. 2006

The Journal of Immunology

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NK cells represent a potent immune effector cell type that have the ability to recognize and lyse tumors. However, the existence and function of NK cells in the traditionally “immune-privileged” CNS is controversial. Furthermore, the cellular interactions involved in NK cell anti-CNS tumor immunity are even less well understood. We administered non-Ag-loaded, immature dendritic cells (DC) to CD8α knockout (KO) mice and studied their anti-CNS tumor immune responses. DC administration induced dramatic antitumor immune protection in CD8α KO mice that were challenged with B16 melanoma both s.c. and in the brain. The CNS antitumor immunity was dependent on both CD4+ T cells and NK cells. Administration of non-Ag-loaded, immature DC resulted in significant CD4+ T cell and NK cell expansion in the draining lymph nodes at 6 days postvaccination, which persisted for 2 wk. Finally, DC administration in CD8α KO mice was associated with robust infiltration of CD4+ T cells and NK cells into the brain tumor parenchyma. These results represent the first demonstration of a potent innate antitumor immune response against CNS tumors in the absence of toxicity. Thus, non-Ag-loaded, immature DC administration, in the setting of CD8 genetically deficient mice, can induce dramatic antitumor immune responses within the CNS that surpass the effects observed in wild-type mice. Our results suggest that a better understanding of the cross-talk between DC and innate immune cells may provide improved methods to vaccinate patients with tumors located both systemically and within the CNS.

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“…For example, murine DC subsets differentially express TLR7, and these expression patterns may result in subset-dependent responses after i.v. administration of TLR7/8 ligands such as the synthetic adjuvant resiquimod (R-848) [15,16]. With respect to migrating DC, especially their subsets, very little is known about expression of TLR and their response to specific TLR ligands in vivo.…”

Section: Introductionmentioning

confidence: 99%

A distinct subset of intestinal dendritic cells responds selectively to oral TLR7/8 stimulation

Yrlid¹,

Cerovic

Milling³

et al. 2006

Eur J Immunol

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The intestinal innate immune system continually interacts with commensal bacteria, thus oral vaccines should induce extra/alternative activation of DC, potentially through TLR. To examine this we collected intestinal lymph DC (iL-DC) under steady-state conditions and after feeding resiquimod (R-848), a synthetic TLR7/8 ligand, which we showed induces complete emptying of gut DC into lymph. iL-DC are heterogeneous with subset-specific functions. In this study we determined the kinetics of iL-DC subset release, activation and cytokine secretion induced by R-848. We show that L-DC comprise three distinct subsets (CD172a high , CD172a int and CD172a low ) present with similar frequencies in intestinal but not hepatic lymph. No iL-DC express TLR7 mRNA, and only CD172a + iL-DC express TLR8. However, after oral R-848 administration, output of all three subsets increases dramatically. CD172a high DC release precedes that of CD172a low DC, and the increased frequency of CD25 high iL-DC is restricted to the two CD172a + subsets. After feeding R-848 only CD172a high iL-DC secrete IL-6 and IL-12p40. However, CD172a int and CD172a high DC secrete similar but markedly lower amounts when stimulated in vitro. These results highlight the importance of in vivo approaches to assess adjuvant effects on DC and give novel insights into the subset-specific effects of an oral TLR ligand on intestinal DC.

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The Immune Response Modifier and Toll-Like Receptor 7 Agonist S-27609 Selectively Induces IL-12 and TNF-α Production in CD11c+CD11b+CD8− Dendritic Cells

Cited by 95 publications

References 70 publications

TNF-α-Dependent and -Independent Maturation of Dendritic Cells and Recruited CD11cintCD11b+ Cells during Oral Salmonella Infection

TNF-α-Dependent and -Independent Maturation of Dendritic Cells and Recruited CD11cintCD11b+ Cells during Oral Salmonella Infection

NK and CD4 Cells Collaborate to Protect against Melanoma Tumor Formation in the Brain

A distinct subset of intestinal dendritic cells responds selectively to oral TLR7/8 stimulation

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