Stimulator of Interferon Genes in Classical Dendritic Cells Controls Mucosal Th17 Responses to Cyclic Dinucleotides for Host Defenses Against Microbial Infections in Gut

Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate arm of the immune system. Dendritic cells initiate and regulate the highly pathogen-specific adaptive immune responses and are central to the development of immunologic memory and tolerance. Recent in vivo experimental approaches in the mouse have unveiled new aspects of the developmental and lineage relationships among these cell populations. Despite this, the origin and differentiation cues for many tissue macrophages, monocytes, and dendritic cell subsets in mice, and the corresponding cell populations in humans, remain to be elucidated.

We describe de novo generation of IL-17-producing T cells from naive CD4 T cells, induced in cocultures of naive CD4 T cells and naturally occurring CD4+ CD25+ T cells (Treg) in the presence of TLR3, TLR4, or TLR9 stimuli. Treg can be substituted by TGFbeta1, which, together with the proinflammatory cytokine IL-6, supports the differentiation of IL-17-producing T cells, a process that is amplified by IL-1beta and TNFalpha. We could not detect a role for IL-23 in the differentiation of IL-17-producing T cells but confirmed its importance for their survival and expansion. Transcription factors GATA-3 and T-bet, as well as its target Hlx, are absent in IL-17-producing T cells, and they do not express the negative regulator for TGFbeta signaling, Smad7. Our data indicate that, in the presence of IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation of IL-17-producing T cells.

Studies of the roles of microbial communities in the development of inflammatory bowel disease (IBD) have reached an important milestone. A decade of genome-wide association studies and other genetic analyses have linked IBD with loci that implicate an aberrant immune response to the intestinal microbiota. More recently, profiling studies of the intestinal microbiome have associated the pathogenesis of IBD with characteristic shifts in the composition of the intestinal microbiota, reinforcing the view that IBD results from altered interactions between intestinal microbes and the mucosal immune system. Enhanced technologies can increase our understanding of the interactions between the host and its resident microbiota and their respective roles in IBD from both a large-scale pathway view and at the metabolic level. We review important microbiome studies of patients with IBD and describe what we have learned about the mechanisms of intestinal microbiota dysfunction. We describe the recent progress in microbiome research from exploratory 16S-based studies, reporting associations of specific organisms with a disease, to more recent studies that have taken a more nuanced view, addressing the function of the microbiota by metagenomic and metabolomic methods. Finally, we propose study designs and methodologies for future investigations of the microbiome in patients with inflammatory gut and autoimmune diseases in general. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.