Different Roles for Human Lung Dendritic Cell Subsets in Pulmonary Immune Defense Mechanisms

Abstract

Dendritic cells (DC) have a central role in the initiation of adequate immune responses. They recognize pathogens by means of Toll-like receptors (TLR) and link innate to adaptive immune responses by releasing proinflammatory cytokines and inducing T cell proliferation. We conducted this study to evaluate the expression and function of TLR on human lung DC subsets and to study their T cell stimulatory capacity. TLR gene expression by human pulmonary DC was evaluated by RT-PCR, while protein expression was analyzed by flow cytometry. We investigated cytokine release by DC in response to different TLR ligands. T cell stimulatory capacity was evaluated by mixed leukocyte reactions of purified lung DC with allogeneic T cells. Myeloid dendritic cells type 1 (mDC1) and myeloid dendritic cells type 2 (mDC2) express mRNA transcripts for TLR1, TLR2, TLR3, TLR4, TLR6, and TLR8. Flow cytometric analysis demonstrated high TLR2 protein expression for mDC1 and moderate TLR4 expression for mDC2. mDC1 and mDC2 release proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, and IL-8) in response to TLR2 and TLR4 ligands. TLR3 ligands induce cytokine release in mDC1, but not in mDC2. Plasmacytoid DC (pDC) express TLR7 and TLR9 and release proinflammatory cytokines in response to imiquimod and IFN-alpha in response to CpG oligonucleotides. mDC1 are strong inducers of T cell proliferation, while pDC hardly induce any T cell proliferation. mDC2 have an intermediate T cell-stimulatory capacity. Our results show divergent roles for the different human lung DC subsets, both in innate and adaptive immune responses.

The Immunopathogenesis of Chronic Obstructive Pulmonary Disease: Insights from Recent Research

“…All four types of DC previously identified in peripheral blood (32,33) have been identified in the lungs. These are: myeloid DC types 1 and 2, which are blood DC antigen 1 ϩ (BDCA1 ϩ ) and BDCA3 ϩ , respectively; plasmacytoid DCs, positive for both the IL-3 receptor (CD123) and BDCA2; and CD1a…”

Plasmacytoid dendritic cells in pulmonary lymphoid follicles of patients with COPD

“…pDCs represent a unique population of professional antigen-presenting cells with a plasma cell-like morphology and a unique surface receptor phenotype, capable of producing large amounts of type I interferons in response to viruses and nucleic acid-containing complexes from the host, sensed through Toll-like receptors (TLRs)-7 and -9 [8,9]. Apart from this innate antiviral defence function, pDCs play a crucial role in maintaining tolerance by expressing the enzyme indoleamine 2,3 dioxygenase which induces T-cell death by depleting the amino acid tryptophan [10].…”

Concomitant Inhalation of Cigarette Smoke and Aerosolized Protein Activates Airway Dendritic Cells and Induces Allergic Airway Inflammation in a TLR-Independent Way

“…The outcome of adaptive immune responses depends on the context in which the Ag is encountered by airway DCs and is predominantly defined by the presence or absence of danger signals at the exposed site, such as pathogen-associated molecular patterns betraying the presence of bacterial, fungal, or viral pathogens and damage-associated molecular patterns released by stressed or damaged host tissue cells (21)(22)(23). TLRs expressed on DCs are essential for the integration of these alarm signals and different pulmonary DC subsets have been shown to express different TLRs, potentially leading to different immunological outcomes (24). Triggering of TLRs leads to DC activation manifested by the up-regulation of a specific set of costimulatory molecules, enhanced migration toward draining LNs, and efficient priming of T cells, which will recirculate to the periphery in an attempt to neutralize the threat.…”