Controls for Lung Dendritic Cell Maturation and Migration during Respiratory Viral Infection

Abstract

Dendritic cells are ideally suited to orchestrate the innate and adaptive immune responses to infection, but we know little about how these cells respond to infection with common respiratory viruses. Paramyxoviral infections are the most frequent cause of serious respiratory illness in childhood and are associated with an increased risk of asthma. We therefore used a high-fidelity mouse model of paramyxoviral respiratory infection triggered by Sendai virus to examine the response of conventional and plasmacytoid dendritic cells (cDCs and pDCs, respectively) in the lung. We found that pDCs are scarce at baseline but become the predominant population of lung dendritic cells during infection. This recruitment allows for a source of IFN-α locally at the site of infection. In contrast, cDCs rapidly differentiate into myeloid cDCs and begin to migrate from the lung to draining lymph nodes within 2 h after viral inoculation. These events cause the number of lung cDCs to decrease rapidly and remain decreased at the site of viral infection. Maturation and migration of lung cDCs depends on Ccl5 and Ccr5 signals because these events are significantly impaired in Ccl5−/− and Ccr5−/− mice. cDCs failure to migrate to draining lymph nodes in Ccl5−/− or Ccr5−/− mice is associated with impaired up-regulation of CCR7 that would normally direct this process. Our results indicate that pDCs and cDCs respond distinctly to respiratory paramyxoviral infection with patterns of movement that should serve to coordinate the innate and adaptive immune responses, respectively.

Characterization of Pulmonary T Cell Response to Helper-Dependent Adenoviral Vectors following Intranasal Delivery

“…Ex vivo studies have further demonstrated that adenovirus can induce IFN-␣ secretion by pDCs via TLR-MyD88 pathway (36). The observation of priming of DC maturation and migration within the first 48 h is consistent with the previous findings involving other respiratory viruses such as paramoxyviruses (22). This may in part explain the role of clinically used mucolytic agent Nacystelyn, which can inhibit DC maturation, in enhancing HD-Ad mediated gene transfer to mouse airways (4,37).…”

“…Maturation of CD8␣ DCs was assessed by gating on CD11c ϩ CD8␣ ϩ cells from the draining lymph nodes and staining with CD86 Ab as a maturation marker. Cells were gated according to their forward scatter vs side scatter characteristics to discriminate highly autofluorescent macrophages from DCs as described previously (22). Flow cytometry data was acquired for each of the experiments using a BD FACSCalibur (BD Biosciences) at the SickKids-University Health Network Flow Cytometry Facility and was analyzed using FlowJo flow cytometry analysis software (Tree Star).…”

CX3CL1 Up-Regulation Is Associated with Recruitment of CX3CR1+ Mononuclear Phagocytes and T Lymphocytes in the Lungs during Cigarette Smoke-Induced Emphysema

“…54,55 We have also noted this property of macrophages by fluorescence microscopy. In addition, the MAC3 antigen is a commonly used marker for macrophages, both by flow cytometry 56 and by immunohistochemical technique. 57 It has been suggested by others , and -12 in lung tissue homogenates after 24 weeks of cigarette smoke exposure.…”

“…45 In contrast to previous findings, we show that macrophages, distinguished from monocytes and dendritic cells by their autofluorescent property and the expression of the MAC3 antigen, are CX3CR1 ϩ in vivo. Furthermore, Grayson and colleagues 56 found that MAC3 ϩ /CD11c ϩ cells in the lungs represent alveolar macrophages that exhibit distinct scatter characteristics from MAC3 ϩ /CD11c Ϫ cells that represent tissue macrophages. Our findings show that both alveolar macrophages (MAC3 ϩ /CD11c ϩ ) and tissue macrophages (MAC3 ϩ /CD11c Ϫ ) expressed CX3CR1 in the lungs.…”

Surfactant protein D inhibits TNF-α production by macrophages and dendritic cells in mice

“…22 In murine models of airway inflammation, 2 subsets appeared particularly interesting. Plasmacytoid dendritic cells make up the majority under baseline conditions, 23 and these cells were shown to be tolerogenic in allergen-induced inflammation. [24][25][26] On the other hand, myeloid dendritic cells migrate rapidly to the lung during T H 2-type inflammation and exert potent T H 2 cell activation.…”