Human Intestinal Lamina Propria CD1c+ Dendritic Cells Display an Activated Phenotype at Steady State and Produce IL-23 in Response to TLR7/8 Stimulation

摘要

Intestinal dendritic cells (DCs) play key roles in mediating tolerance to commensal flora and inflammatory responses against mucosal pathogens. The mechanisms by which intestinal “conditioning” influences human DC responses to microbial stimuli remain poorly understood. Infections with viruses, such as HIV-1, that target mucosal tissue result in intestinal epithelial barrier breakdown and increased translocation of commensal bacteria into the lamina propria (LP). It is unclear whether innate LP DC responses to concurrent viral and bacterial stimuli influence mucosal HIV-1 pathogenesis. In this study, direct ex vivo phenotype and in vitro constitutive cytokine production of CD1c+ DCs in human intestinal LP were compared with those in peripheral blood (PB). To evaluate innate responses to viral and bacterial stimuli, intracellular cytokine production by LP and PB DCs following stimulation with ligands for TLRs 2, 4, 5, and 7/8 was evaluated. At steady state, LP CD1c+ DCs expressed higher levels of activation markers (CD40, CD83, CD86, HLA-DR, and CCR7) than did PB CD1c+ DCs, and higher frequencies of LP CD1c+ DCs constitutively produced IL-6 and -10 and TNF-α. LP DCs had blunted cytokine responses to TLR4 ligand and TLR5 ligand stimulation relative to PB DCs, yet similarly produced IL-10 in response to TLR2 ligand. Only synthetic TLR7/8 ligand, a mimic of viral ssRNA, induced IL-23 production by LP CD1c+ DCs, and this proinflammatory cytokine response was synergistically enhanced following combined TLR7/8 and TLR4 stimulation. These findings highlight a potential mechanism by which viruses like HIV-1 may subvert homeostatic mechanisms and induce inflammation in the intestinal mucosa.