Clearance of influenza virus from the lung depends on migratory langerin+CD11b− but not plasmacytoid dendritic cells

Abstract

Although dendritic cells (DCs) play an important role in mediating protection against infl uenza virus, the precise role of lung DC subsets, such as CD11b ؊ and CD11b + conventional DCs or plasmacytoid DCs (pDCs), in different lung compartments is currently unknown. Early after intranasal infection, tracheal CD11b ؊ CD11c hi DCs migrated to the mediastinal lymph nodes (MLNs), acquiring co-stimulatory molecules in the process. This emigration from the lung was followed by an accumulation of CD11b + CD11c hi DCs in the trachea and lung interstitium. In the MLNs, the CD11b + DCs contained abundant viral nucleoprotein (NP), but these cells failed to present antigen to CD4 or CD8 T cells, whereas resident CD11b ؊ CD8 ␣ + DCs presented to CD8 cells, and migratory CD11b ؊ CD8 ␣ ؊ DCs presented to CD4 and CD8 T cells. When lung CD11c hi DCs and macrophages or langerin + CD11b ؊ CD11c hi DCs were depleted using either CD11c -diphtheria toxin receptor (DTR) or langerin-DTR mice, the development of virus-specifi c CD8 + T cells was severely delayed, which correlated with increased clinical severity and a delayed viral clearance. 120G8 + CD11c int pDCs also accumulated in the lung and LNs carrying viral NP, but in their absence, there was no effect on viral clearance or clinical severity. Rather, in pDC-depleted mice, there was a reduction in antiviral antibody production after lung clearance of the virus. This suggests that multiple DCs are endowed with different tasks in mediating protection against infl uenza virus.on

Insights into Langerhans cell function from Langerhans cell ablation models

“…Interestingly, Langerin 1 dDC are phenotypically very similar to Langerin 1 DC populations found in the lung, and it is yet unclear whether these two populations are mutually exclusive or together constitute a Langerin 1 interstitial DC subset [36,40]. Recent experiments demonstrate that clearance of influenza virus from the lung depends on this migratory Langerin 1 DC subset [43]. They generated chimeras using F1 (C57BL/6 I-A b-/-Â BALB/c I-E d1 ) mice reconstituted with C57BL/6 I-A b1/1 BM; thus only donor cells and not LC would be capable of presenting I-E dderived peptide.…”

Origin and functional specializations of DC subsets in the lung

“…These cells express CD103(aEb7) and langerin [2]. Immediately below, the lamina propria contains CD11b hi cDC [3][4][5] that express the SIRPa molecule (a ligand of CD47), and the CX3CR1 fractalkine receptor [6,7].…”

“…Immediately below, the lamina propria contains CD11b hi cDC [3][4][5] that express the SIRPa molecule (a ligand of CD47), and the CX3CR1 fractalkine receptor [6,7]. The conducting airways also contain pDC, best identified by additional staining for Siglec-H, or bone-marrow stromal antigen-2 (BST2) [1,2,8,9].…”

“…As these monocyte-derived cells retain expression of Ly6C, we advise the use of Ly6C to discriminate these newly recruited cells from resident CD11b 1 cDC [2,5,14].…”

“…As only one example, the pDC 'specific' marker BST2 (recognized by moAb 120G8) is massively upregulated on CD11b 1 inflammatory DC and B cells, most likely under the influence of type I interferons released upon innate immune response activation [14]. Therefore we strongly advise the use of multiparameter flow cytometry (using up to ten markers) to reliably identify DC subsets and their close relative, the macrophages in the lung [2,13,14].…”