Adaptive immune responses in intestinal homeostasis and experimental inflammatory bowel disease
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The intestine, a dwelling place for trillions of commensal bacteria, is constantly exposed to numerous ligands and antigens from foods and microbiota. Intestinal homeostasis involves a balance between anti-inflammatory and pro-inflammatory signals. Intestinal epithelial barrier, commensal bacteria, and immune cells, along with the interactions between the three players maintain a toleranic environment to food and microbiota. Conversely, when a dysregulated interaction occurs in genetically susceptible individuals, the homeostasis breaks down and chronic intestinal inflammation develops. CD4+ T cells are important mediators for both intestinal homeostasis and colitis development. The intestine is a preferential site for induction of Treg, Th1 and Th17 cells. The differentiation, plasticity and functions of CD4+ T cells in intestines are intensely studied, but still incompletely defined. The differentiation of peripherally induced Tregs and Th17 cell population is reciprocally regulated in the intestine. In addition to the regulation by master transcriptional factors and STATS signaling, the ERK pathway is also involved in regulating or fine-tuning T cell lineage commitment. ERK differentially regulates Tregs and Th17 cell development by positively regulating Th17 and negatively regulating Treg cell differentiation. My studies indicated that the inhibition of ERK decreased IL-6 induction of RORγt while it enhanced TGF-β induction of Foxp3. Moreover, ERK inhibitor-treated T cells under Th17 conditions possessed a suppressive function in vitro because they produced more IL-10 and TGF-β. Furthermore, ERK inhibitor-treated T cells under Th17 polarization conditions had a decreased potency to induce colitis in vivo. Although accumulating evidence demonstrates that differentiated CD4+ T cells preserve plasticity to alter phenotypes under various conditions, it is still unclear how stable Th1 cells are and whether Th1 cells can convert into Th17 cells. I demonstrated that Th1 cells converted into Th17 cells under inflammatory conditions in the mouse intestines. TGF-β, IL-6 and IL-2, but not hypoxia factors, differentially regulated Th1 to Th17 conversion. TGF-β induction of Runx1 and RORγt, was crucial for the conversion. Taken together, my studies revealed the interference with the ERK pathway could represent a therapeutic treatment for inflammatory bowel diseases and demonstrated that Th1 cells convert into Th17 cells under inflammatory conditions in intestines, which was mediated by TGF-β induction of Runx1.