IRF4 Promotes Cutaneous Dendritic Cell Migration to Lymph Nodes during Homeostasis and Inflammation

Bajaña, Sandra; Roach, Kimberly; Turner, Seán; Paul, Jinny; Kovats, Susan

doi:10.4049/jimmunol.1102613

Cited by 146 publications

(170 citation statements)

References 34 publications

(58 reference statements)

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“…Nb-loaded DC were CD301b + and expressed higher levels of PDL2 compared with other DC or DC from PBS-treated mice, suggesting a preferential involvement of such a subset in the Nb-induced response. The transcription factor IRF4, which is required for the maturation, migration, and function of skin DC in LN (25,49,50), was also expressed, but its levels were similar in all DC regardless of Nb loading or treatment. This latter finding aligns with recent reports showing that IRF4 is necessary for the generation of Th2 responses (25,51), but also suggests that IRF4 is unlikely to represent a polarizing signal that determines the ability of DC from Nb-treated mice to prime for IL-4 production.…”

Section: Discussionmentioning

confidence: 99%

Helminth-Conditioned Dendritic Cells Prime CD4+ T Cells to IL-4 Production In Vivo

Connor

Tang

Camberis

et al. 2014

The Journal of Immunology

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Dendritic cells (DC) are critical for the initiation of immune responses; however, their role in priming IL-4–producing Th2 cells in vivo is not fully understood. We used a model of intradermal injection with fluorescent-labeled, nonviable larvae from the helminth parasite nonviable Nippostrongylus brasiliensis L3 larvae (Nb), a strong inducer of Th2 responses, together with IL-4–GFP reporter mice that enable a sensitive detection of IL-4 production to examine the contribution of DC to the priming of IL-4–producing CD4+ T cells in vivo. We found that parasite material is taken up by two distinct DC populations in draining lymph nodes: a mostly CD11cintMHC class II (MHCII)hiCD11b+Ly6C− dermal DC population and a CD11chiMHCIIintCD11b+Ly6C+ monocyte-derived DC population. After Nb treatment, these two DC populations appeared in the draining lymph nodes in comparable numbers and with similar kinetics; however, treatment with pertussis toxin blocked the migration of dermal DC and the priming of IL-4–producing T cells, but only partially affected monocyte-derived DC numbers. In line with this observation, transfer of OVA-loaded CD11cintMHCIIhi DC from Nb-treated mice into naive hosts could sensitize OVA-specific CD4+ T cells to IL-4 production, whereas transfer of CD11cintMHCIIhi DC from naive mice, or CD11chiMHCIIint DC from Nb-treated or naive mice, induced CD4+ T cell expansion but no IL-4 production. Phenotypic analysis of Nb-loaded CD11cintMHCIIhi DC revealed expression of programmed death ligand 2, CD301b, IFN regulatory factor 4, and moderate upregulation of OX40 ligand. However, thymic stromal lymphopoietin and OX40 ligand were not required for Th2 priming. Thus, our data suggest that appropriate stimuli can induce DC to express the unique signals sufficient to direct CD4+ T cells to Th2 differentiation.

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Section: Discussionmentioning

confidence: 99%

Helminth-Conditioned Dendritic Cells Prime CD4+ T Cells to IL-4 Production In Vivo

Connor

Tang

Camberis

et al. 2014

The Journal of Immunology

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“…CCR7 expression was reduced in mDCs lacking IRF4, consistent with the reduced ability of these DCs to migrate to the LNs. While this study was in progress, Bajaña et al (23) reported that migration of CD11b + DCs, as well as Langerhans cells, from the dermis to LNs was impaired in Irf4 2/2 mice. Our study using Irf4 fl/fl CD11c-Cre mice is consistent with their study and further shows that the defective migration of DCs occurs independently of the IRF4 defect in the lymphocyte compartment.…”

Section: Discussionmentioning

confidence: 99%

“…Bajaña et al (23) reported that IRF4 is critical for the CCR7-mediated migration of CD11b + DCs from the dermis to LNs. Recent studies (41,42) suggest that IRF4 in DCs is critical for the survival of a subset of CD11b + DCs in the lamina propria of the intestine and lung, as well as mesenteric LNs, and support Th17 differentiation after immunization or infection.…”

Section: Discussionmentioning

confidence: 99%

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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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“…1E). To evaluate DC trafficking from the skin to the LN, we infected well-nourished and malnourished mice with L. donovani and, immediately after the parasite inoculation, painted the skin site with a fluorescent marker (CMFDA or CMTMR) so that labeled dermal DCs that had migrated to the draining LN could be distinguished from DCs already resident in the LN (27,29,30). Control experiments demonstrated highly efficient and equivalent labeling of migratory skin DCs in the wellnourished and malnourished mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Deficiency of Lymph Node-Resident Dendritic Cells (DCs) and Dysregulation of DC Chemoattractants in a Malnourished Mouse Model of Leishmania donovani Infection

et al. 2014

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Malnutrition is thought to contribute to more than one-third of all childhood deaths via increased susceptibility to infection. Malnutrition is a significant risk factor for the development of visceral leishmaniasis, which results from skin inoculation of the intracellular protozoan Leishmania donovani. We previously established a murine model of childhood malnutrition and found that malnutrition decreased the lymph node barrier function and increased the early dissemination of L. donovani. In the present study, we found reduced numbers of resident dendritic cells (conventional and monocyte derived) but not migratory dermal dendritic cells in the skin-draining lymph nodes of L. donovani-infected malnourished mice. Expression of chemokines and their receptors involved in trafficking of dendritic cells and their progenitors to the lymph nodes was dysregulated. C-C chemokine receptor type 2 (CCR2) and its ligands (CCL2 and CCL7) were reduced in the lymph nodes of infected malnourished mice, as were CCR2-bearing monocytes/macrophages and monocyte-derived dendritic cells. However, CCR7 and its ligands (CCL19 and CCL21) were increased in the lymph node and CCR7 was increased in lymph node macrophages and dendritic cells. CCR2-deficient mice recapitulated the profound reduction in the number of resident (but not migratory dermal) dendritic cells in the lymph node but showed no alteration in the expression of CCL19 and CCL21. Collectively, these results suggest that the malnutrition-related reduction in the lymph node barrier to dissemination of L. donovani is related to insufficient numbers of lymph node-resident but not migratory dermal dendritic cells. This is likely driven by the altered activity of the CCR2 and CCR7 chemoattractant pathways.

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IRF4 Promotes Cutaneous Dendritic Cell Migration to Lymph Nodes during Homeostasis and Inflammation

Cited by 146 publications

References 34 publications

Helminth-Conditioned Dendritic Cells Prime CD4+ T Cells to IL-4 Production In Vivo

Helminth-Conditioned Dendritic Cells Prime CD4+ T Cells to IL-4 Production In Vivo

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

Deficiency of Lymph Node-Resident Dendritic Cells (DCs) and Dysregulation of DC Chemoattractants in a Malnourished Mouse Model of Leishmania donovani Infection

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