Two waves of antigen‐containing dendritic cells <i>in vivo</i> in experimental <i>Leishmania major</i> infection

Misslitz, Ana Clara; Bonhagen, Kerstin; Harbecke, Dorothee; Lippuner, Christoph; Kamradt, Thomas; Aebischer, Toni

doi:10.1002/eji.200324391

Cited by 60 publications

(57 citation statements)

References 40 publications

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“…Our observation of an emigrant population of DC from the skin accumulating in lymph nodes after peripheral Ag deposition in the skin is in agreement with prior observations in other systems (32)(33)(34)(35). Although a number of DC subsets have been implicated in Th cell differentiation, it remains unclear whether skin-emigrant DC populations are truly responsible for Th cell activation in situ.…”

Section: Populations Activated To Express Il-12/23p40 Migrate Moresupporting

confidence: 91%

“…This population peaks around 12-16 h after LPS injection or 48 h after Listeria inoculation, correlating with the second wave of activated DC in draining lymph nodes indicated by prior studies (32,34). In those studies, the second wave represents emigration from sites of Ag deposition, as opposed to the first wave, which represents activation of resident DC in the lymph node, presumably in response to soluble Ags and cytokines arriving via afferent lymphatics.…”

Section: Discussionmentioning

confidence: 56%

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Visualization of IL-12/23p40 In Vivo Reveals Immunostimulatory Dendritic Cell Migrants that Promote Th1 Differentiation

Reinhardt

Hong

Kang

et al. 2006

The Journal of Immunology

104

100

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IL-12p40 is induced in macrophages and dendritic cells (DC) after activation by microbial TLR ligands and cytokines and constitutes a component of IL-12 and IL-23. In an effort to understand the location and kinetics of these cytokines during the course of an immune response, we generated knockin (gene-targeted) mice that express the p40 gene linked via a viral internal ribosome entry site element with fluorescent reporters, eYFP or eGFP. Macrophages and DC from these mice faithfully reported biallelic p40 induction using the fluorescent marker. s.c. inoculation with Listeria monocytogenes or LPS led to a rapid, but transient, accumulation of p40-expressing DC in draining lymph nodes, which could be blocked by the addition of pertussis toxin. In situ analysis also revealed the accumulation of IL-12p40 protein around high endothelial venules located in close proximity to p40-expressing DC. Consistent with the in vivo findings, in vitro-activated DC that expressed p40 migrated to draining lymph nodes and promoted Th1 differentiation more efficiently than DC that did not express p40. Accordingly, these mice provide a valuable tool for tracking critical functions of DC in vivo and should bestow a useful reagent for exploring the effector biology of these cells in models of infectious disease, cancer immunity, and vaccine development.

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Section: Populations Activated To Express Il-12/23p40 Migrate Moresupporting

confidence: 91%

Section: Discussionmentioning

confidence: 56%

Visualization of IL-12/23p40 In Vivo Reveals Immunostimulatory Dendritic Cell Migrants that Promote Th1 Differentiation

Reinhardt

Hong

Kang

et al. 2006

The Journal of Immunology

104

100

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“…During the early phase of infection, DCs that initiate parasite-specific immune response in the draining LNs are not directly infected with L. major. CD11c hi CD11b hi Langerin 2 resident DCs in the LNs acquire soluble Leishmania Ags released by parasites and present these Ags to specific CD4 + T cells, while, at the same time, producing IL-12 (5,6). Several days postinfection, CD8…”

Section: Irf4 In Dendritic Cells Inhibits Il-12 Production and Contromentioning

confidence: 99%

IRF4 in Dendritic Cells Inhibits IL-12 Production and Controls Th1 Immune Responses against Leishmania major

Akbari

Honma

Kimura

et al. 2014

The Journal of Immunology

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IRF4 is a transcription factor from the IRF factor family that plays pivotal roles in the differentiation and function of T and B lymphocytes. Although IRF4 is also expressed in dendritic cells (DCs) and macrophages, its roles in these cells in vivo are not clearly understood. In this study, conditional knockout mice that lack IRF4 in DCs or macrophages were generated and infected with Leishmania major. Mice lacking DC expression of IRF4 showed reduced footpad swelling compared with C57BL/6 mice, whereas those lacking IRF4 in macrophages did not. Mice with IRF4-deficient DCs also showed reduced parasite burden, and their CD4+ T cells produced higher levels of IFN-γ in response to L. major Ag. In the draining lymph nodes, the proportion of activated CD4+ T cells in these mice was similar to that in the control, but the proportion of IFN-γ–producing cells was increased, suggesting a Th1 bias in the immune response. Moreover, the numbers of migrating Langerhans cells and other migratory DCs in the draining lymph nodes were reduced both before and postinfection in mice with IRF4 defects in DCs, but higher levels of IL-12 were observed in IRF4-deficient DCs. These results imply that IRF4 expression in DCs inhibits their ability to produce IL-12 while promoting their migratory behavior, thus regulating CD4+ T cell responses against local infection with L. major.

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“…Draining LN of mice infected with L. mexicana wild-type or lpg1-deficient parasites were collected 16 h post-infection, fixed and processed as described [53]. Briefly, sections were incubated with an anti-L. mexicana rabbit serum, anti-DEC205 (NLDC145, rat IgG2a) to detect DC and a combination of anti-IL-12p40 Ab (C17.8, rat IgG2a and C15.6, rat IgG1) to visualize IL-12p40.…”

Section: Immunofluorescencementioning

confidence: 99%

A critical role for lipophosphoglycan in proinflammatory responses of dendritic cells to Leishmania mexicana

et al. 2005

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Recognition of pathogen-associated molecular patterns (PAMP) influences the response of dendritic cells (DC) and therefore development of innate and adaptive immunity. Different forms of Leishmania mexicana have distinct effects on DC, with promastigotes and amastigotes being activating and apparently neutral, respectively. We investigated whether stage-specific differences in surface composition might account for these distinct effects. Amastigotes and promastigotes lacking the lpg1 gene needed for lipophosphoglycan (LPG) biosynthesis could not activate DC in vitro. Genome-wide transcriptional profiling of DC infected with wild-type or mutant promastigotes or wildtype amastigotes revealed that wild-type promastigotes induce an inflammatory signature that is lacking in DC exposed to the other parasite forms. The proinflammatory response pattern was partly recovered by reconstitution of lpg1 expression in lpg1 -/-parasites, and exposure to purified LPG increased the expression of MHC class II and CD86 on DC. Infection with wild-type but not lpg1 -/-promastigotes increased the number of activated DC in draining lymph nodes, and this was correlated with lower early parasite burdens in wild-type-infected animals. These in vivo and in vitro results suggest an LPG-dependent activation of DC that contributes to host defense and agree with the notion that the parasites evolved under immune pressure to downregulate PAMP expression in mammalian hosts.

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Two waves of antigen‐containing dendritic cells in vivo in experimental Leishmania major infection

Cited by 60 publications

References 40 publications

Visualization of IL-12/23p40 In Vivo Reveals Immunostimulatory Dendritic Cell Migrants that Promote Th1 Differentiation

Visualization of IL-12/23p40 In Vivo Reveals Immunostimulatory Dendritic Cell Migrants that Promote Th1 Differentiation

IRF4 in Dendritic Cells Inhibits IL-12 Production and Controls Th1 Immune Responses against Leishmania major

A critical role for lipophosphoglycan in proinflammatory responses of dendritic cells to Leishmania mexicana

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