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

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.