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accumulation, depletion of these Ly6C + monocytes did not inhibit inflammatory gene expression suggesting an alternative source for inflammatory cytokines in this model. We hypothesize that microbial-dependent skewing of intestinal Ly6C 2 macrophages rather than accumulation of Ly6C + monocytes in the absence of IL10R may play a central role in driving colonic inflammation in neonates that lack IL10R. We suggest that further mechanistic studies using the described novel IL10R-deficient neonatal models may lead to novel insights into the pathogenesis of both neonatal and adult onset IBD.

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revealed an allele-specific preference in protein binding at this site of CD-specific open chromatin. CONCLUSIONS: We demonstrate that different genomic loci exhibit distinct chromatin changes that play active roles in shaping the response in LP macrophages to the enteric microbiota. These chromatin features are dynamic and regulated by IL-10 and the enteric microbiota. These findings introduce the possibility of modulating chromatin regulators with small molecules for the treatment of CD.BACKGROUND: The FVB.mdr1a2/2 mouse, lacking the small molecule pump Pglycoprotein (P-gp), is a commonly used model for the study of spontaneous T cell mediated colitis. In addition, MDR1 polymorphisms and decreased P-gp function in humans has been linked to the development of ulcerative colitis. Since P-gp is expressed on the apical epithelium of organs and due to the role of P-gp in toxin extrusion, we have hypothesized that P-gp's physiological function is to extrude xenobiotic substrates from the internal environment. The absence of P-gp results in an alteration of the epithelial barrier, increasing permeability to ions, bacterial toxins, and other molecules that could potentially include environmental aryl hydrocarbon receptor (AhR) ligands. This study aims to determine the mechanism by which intestinal inflammation develops in FVB.mdr1a2/2 mice. METHODS: We have utilized the FVB.mdr1a2/2 mouse to investigate the development of individual T-cell subsets in the presence or absence of the AhR ligand 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin (TCDD). T-helper cell development has been evaluated by flow cytometry, RT-PCR, explants, and ELISAs. RESULTS: Recently, our lab has shown that FVB.mdr1a2/2 mice, prior to the development of histological inflammation, have a significant decrease in Foxp3+ regulatory T cells (Tregs) in Peyer's patches (PP) and intestinal lamina propria, but not in spleen and mesenteric lymph nodes (MLN). This decrease in Tregs appears to be due to an inappropriate response to the regulatory cytokine, transforming growth factor beta (TGFb), a cytokine known to be responsible for induced Treg (iTreg) generation. Naïve T-cells from the FVB.mdr1a-/-mouse, when exposed to TGFb, produce IL17 instead of increasing their expression of FoxP3. To further investigate this response and to determine if P-gp alters the impact of AhR ligands on immune responses we treated explants and CD4+ T-cells from FVB and FVB.mdr1a2/2 mice with TCDD. As has been previously reported, the control FVB mice reduced the projection of the TH17 cytokines IL17 and IL22 when exposed to TCDD. However, in the absence of Pgp, TCDD treatment had the opposite effect. There was a dramatic increase in both IL22 and IL17. CONCLUSIONS: This opposite effect of TCDD on cytokine production is the absence of P-gp is consistent with our hypothesis that the P-gp pump is necessary in normal intestinal homeostasis to extrude AhR ligands, such as TCDD.

Inflammatory bowel diseases (IBD) are thought to arise from an overly aggressive immune response to the intestinal microbiota. Campylobacter jejuni is a human enteric pathogen that is a major cause of gastroenteritis worldwide. C. jejuni infection also increases the risk of developing IBD-like sequelae. Prior studies showed IL-10 deficient mice develop fulminant colitis when infected by C. jejuni. However, the roles of adaptive and innate immune cells in promoting colitis remain unresolved. Here, we show that T cells are not necessary for C. jejuni-induced colitis. In vivo depletion of Thy1+ cells or neutralization of IFNγ in T cell deficient mice significantly ameliorated C. jejuni-induced colitis, indicating a pathogenic role for IFNγ-producing innate lymphoid cells (ILC1s). In mice, ILC1s are currently identified as NK1.1+NKp46+ cells and prior studies reported that depleting NK1.1+ cells ameliorated ILC1-driven colitis. Unexpectedly, despite effective depletion of NK1.1+ cells in mice lacking T cells, this treatment did not impact IFNγ production or colon pathology after C. jejuni infection. Phenotyping analysis revealed IFNγ-producing ILCs (Thy1+Lin−Tbet+Eomes−GnzA−RORγtlow/−) that accumulated in the colon during C. jejuni-induced colitis did not express NK1.1 or NKp46. Further, mice deficient for the transcription factor RORγt possessed markedly fewer NK1.1−NKp46− ILC1s in the intestine and exhibited reduced severity of C. jejuni-induced colitis. Based on the lack of NK and natural cytotoxicity receptors (NCR) and in accord with the current ILC nomenclature, we propose the tentative designation of NCR−ILC1. Together, these results identified a unique population of ILC1s that promote colitis.