Complement Receptor C5aR1/CD88 and Dipeptidyl Peptidase-4/CD26 Define Distinct Hematopoietic Lineages of Dendritic Cells

Nakano, Hideki; Moran, Timothy P.; Nakano, Keiko; Gerrish, Kevin; Bortner, Carl D.; Cook, Donald N.

doi:10.4049/jimmunol.1402195

Cited by 52 publications

(61 citation statements)

References 53 publications

(103 reference statements)

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“…To confirm this, we stained lung slices with antibodies against CD103, Sirp1α and CD88. The latter two markers were used to distinguish CD11b + cDCs, which are Sirp1α + CD88 − , from CD88 + macrophages or neutrophils 30 . Using 3D rendering of high power images, we confirmed that both CD103 + and CD11b + cDCs physically interact with Tomato + Th17 cells in the lungs (Figure 6C and Supplementary Videos).…”

Section: Resultsmentioning

confidence: 99%

“…To determine if high amounts of Th17-promoting cytokines in the two cDC subsets could explain their ability to drive Th17 expansion and production of IL-17 ex vivo , we compared expression of Il23p19 , Il1a , Il1b and Il6 in various lung APCs in a microarray database (http://www.ncbi.nlm.nih.gov/geo/info/linking.html; accession no. GSE64896) 30 . CD11b + cDCs expressed the highest amounts of Il1b RNA (Figure 6E).…”

Section: Resultsmentioning

confidence: 99%

“…Cell viability was determined using 7-AAD or APC-eFluor 780 fixable viability dye. Conventional DCs were identified as non-autofluorescent, Siglec F − CD88 − CD11c + I-A b hi cells 30 , as shown in Supplementary Figure 2. Stained cells were acquired on an LSRII flow cytometer using Diva software (BD Biosciences), or sorted using a BD FACS Aria II (purity of the sorted populations was >95%).…”

Section: Methodsmentioning

confidence: 99%

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Pathogenic TH17 inflammation is sustained in the lungs by conventional dendritic cells and Toll-like receptor 4 signaling

Shalaby

Lyons-Cohen

Whitehead

et al. 2018

Journal of Allergy and Clinical Immunology

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Background Mechanisms that elicit mucosal Th17 cell responses have been described, yet how these cells are sustained in chronically inflamed tissues remains unclear. Objective We sought to understand whether the maintenance of lung Th17 inflammation requires environmental agents in addition to antigen, and to identify the lung antigen-presenting cell types (APCs) that sustain the self-renewal of Th17 cells. Methods Animals were repeatedly exposed to aspiration of ovalbumin alone, or together with environmental adjuvants, including extracts of common house dust (HDE), to test their role in maintaining lung inflammation. Alternatively, antigen-specific effector/memory Th17 cells, generated in culture using CD4+ T cells from Il17a fate-mapping mice, were adoptively transferred to assess their persistence in genetically modified animals lacking distinct lung APC subsets or cell-specific TLR4 signaling. Th17 cells were also co-cultured with lung APC subsets to determine which of these could revive their expansion and activation. Results Th17 cells and consequent neutrophilic inflammation were poorly sustained by inhaled antigen alone, but were augmented by inhalation of antigen together with HDE. This was associated with weight loss and changes in lung physiology consistent with interstitial lung disease. The effect of HDE required TLR4 signaling predominantly in lung hematopoietic cells, including CD11c+ cells. CD103+ and CD11b+ conventional dendritic cells (cDCs) directly interacted with Th17 cells in situ and revived the clonal expansion of Th17 cells ex vivo and in vivo, whereas lung macrophages and B cells could not. Conclusion Th17-dependent inflammation in the lungs can be sustained by persistent TLR4-mediated activation of lung cDCs.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Pathogenic TH17 inflammation is sustained in the lungs by conventional dendritic cells and Toll-like receptor 4 signaling

Shalaby

Lyons-Cohen

Whitehead

et al. 2018

Journal of Allergy and Clinical Immunology

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“…The CD11b − DCs express CD8α + in the spleen and CD103 + in nonlymphoid tissues and require IRF8 and BATF3 for their terminal differentiation (19). CD11c + CD11b + MHCII + cells are heterogeneous in nonlymphoid tissues, and the definition of specific DC subsets has only recently been clarified by approaches to separate true CD11b + CD24 + cDC2s from macrophages and monocyte-derived DCs (20–22). Because of this diversity, it has been more difficult to discern the transcription factor networks required for terminal differentiation of the cDC2s and other CD11c + CD11b + subsets.…”

Section: Introductionmentioning

confidence: 99%

IRF4 and IRF8 Act in CD11c+ Cells To Regulate Terminal Differentiation of Lung Tissue Dendritic Cells

Bajaña

Turner

Paul

et al. 2016

The Journal of Immunology

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Dendritic cells (DCs) initiate immune responses in barrier tissues including lung and skin. Conventional DC subsets, CD11b− (cDC1s) or CD11b+ (cDC2s), arise via distinct networks of transcription factors involving IRF4 and IRF8 and are specialized for unique functional responses. Using mice in which a conditional Irf4 or Irf8 allele is deleted in CD11c+ cells, we determined if IRF4 or IRF8 deficiency beginning in CD11c+ cDC precursors (pre-cDCs) changed the homeostasis of mature DCs or pre-DCs in the lung, dermis and spleen. CD11c-cre-Irf4−/− mice selectively lacked a lung-resident CD11chiCD11b+SIRPα+CD24+ DC subset, but not other lung CD11b+ DCs or alveolar macrophages. Numbers of CD11b+CD4+ splenic DCs, but not CD11b+ dermal DCs, were reduced, indicating cDC2s in the lung and dermis develop via different pathways. Irf4 deficiency did not alter numbers of cDC1s. CD11c-cre-Irf8−/− mice lacked lung-resident CD103+ DCs and splenic CD8α+ DCs, yet harbored increased IRF4-dependent DCs. This correlated with a reduced number of Irf8−/− pre-cDCs, which contained elevated IRF4, suggesting that Irf8 deficiency diverts pre-cDC fate. Analyses of Irf4 and Irf8 haploinsufficient mice showed that while one Irf4 allele was sufficient for lung cDC2 development, two functional Irf8 alleles were required for differentiation of lung cDC1s. Thus, IRF8 and IRF4 act in pre-cDCs to direct the terminal differentiation of cDC1 and cDC2 subsets in the lung and spleen. These data suggest that variation in IRF4 or IRF8 levels resulting from genetic polymorphisms or environmental cues will govern tissue DC numbers and therefore regulate the magnitude of DC functional responses.

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“…For unknown reasons, however, not all cDCs that acquire inhaled antigens leave the lung, and many of these cells remain in that organ for several months 5,6 . This observation can be partly explained by the developmental ancestry of these cells because monocyte-derived CD11c + cells lacking the chemokine receptor, CCR7, are unable to migrate to regional LNs 7,8 . It seems likely that the migration potential of cDCs is also determined, at least in part, by their anatomical position within the lung.…”

Section: Introductionmentioning

confidence: 99%

Precision-cut Mouse Lung Slices to Visualize Live Pulmonary Dendritic Cells

Lyons-Cohen

Thomas

Cook

et al. 2017

JoVE

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SHORT ABSTRACT We describe a method for generating precision-cut lung slices (PCLS) and immunostaining them to visualize the localization of various immune cell types in the lung. Our protocol can be extended to visualize the location and function of many different cell types under a variety of conditions. LONG ABSTRACT Inhalation of allergens and pathogens elicits multiple changes in a variety of immune cell types in the lung. Flow cytometry is a powerful technique for quantitative analysis of cell surface proteins on immune cells, but it provides no information on the localization and migration patterns of these cells within the lung. Similarly, in vitro chemotaxis assays can be performed to study the potential of cells to respond to chemotactic factors in vitro, but these assays do not reproduce the complex environment of the intact lung. In contrast to these aforementioned techniques, the location of individual cell types within the lung can be readily visualized by generating precision-cut lung slices (PCLS), staining them with commercially available, fluorescently tagged antibodies, and visualizing the sections by confocal microscopy. PCLS can be used for both live and fixed lung tissue, and the slices can encompass areas as large as a cross section of an entire lobe. We have used this protocol to successfully visualize the location of a wide variety of cell types in the lung, including distinct types of dendritic cells, macrophages, neutrophils, T cells and B cells, as well as structural cells such as lymphatic, endothelial, and epithelial cells. The ability to visualize cellular interactions, such as those between dendritic cells and T cells, in live, three-dimensional lung tissue, can reveal how cells move within the lung and interact with one another at steady state and during inflammation. Thus, when used in combination with other procedures, such as flow cytometry and quantitative PCR, PCLS can contribute to a comprehensive understanding of cellular events that underlie allergic and inflammatory diseases of the lung.

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Complement Receptor C5aR1/CD88 and Dipeptidyl Peptidase-4/CD26 Define Distinct Hematopoietic Lineages of Dendritic Cells

Cited by 52 publications

References 53 publications

Pathogenic TH17 inflammation is sustained in the lungs by conventional dendritic cells and Toll-like receptor 4 signaling

Pathogenic TH17 inflammation is sustained in the lungs by conventional dendritic cells and Toll-like receptor 4 signaling

IRF4 and IRF8 Act in CD11c+ Cells To Regulate Terminal Differentiation of Lung Tissue Dendritic Cells

Precision-cut Mouse Lung Slices to Visualize Live Pulmonary Dendritic Cells

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