Limiting host-microbiota interactions to control intestinal inflammation


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The host intestinal tract lives in constant balance with the commensal microbiota residing in the intestinal lumen and immune responses must be tightly controlled. A strong intestinal barrier separates the immune system from resident microflora, and multiple mechanisms exist to reinforce the epithelium to limit microbial exposure to the immune system, including a thick mucus layer, secretion of antimicrobial peptides, and production of IgA. However, how Th17 cells contribute to intestinal immunity is still largely unknown. Our current studies indicate that Th17 cells play a critical role in controlling microbial contact with the epithelium. IgA is produced in large quantities and secreted into the intestinal lumen where it neutralizes pathogens and prevents microbes from penetrating the epithelium and inducing inflammatory responses. IgA must be actively secreted by epithelial cells after binding to the polymeric immunoglobulin receptor (pIgR), and is limited by the rate of pIgR expression and translocation. Th17 cells can directly induce pIgR expression from intestinal epithelial cells, and increase levels of luminal IgA. During episodes of intestinal injury, the induction of pIgR and increase in IgA as mediated by Th17 cells affords increased protection against microbial breach and infection, thereby preventing inflammatory responses. Keeping the intestinal lamina propria clear of microbial ligands is critical for maintaining intestinal homeostasis and preventing the onset of colitis. We showed that the presence of LPS can inhibit regulatory T cell generation, thereby disrupting immune regulation and clearing a path for unchecked inflammatory responses. TLR4 signaling through both antigen-presenting cells, and on T cells themselves is capable of inhibiting regulatory T cell generation. Upon the induction of a chronically inflamed state, regulatory T cell function is altered and hinders restoration of tissue homeostasis. We show that chronically-inflamed tissues contain increased numbers of regulatory T cells that have acquired effector T cell capability through production of inflammatory cytokines, while retaining a regulatory T cell phenotype. Taken together, our studies reveal a dynamic interaction between the host intestinal environment and microbiota. Understanding of these mechanisms before and after the onset of colitis may direct therapeutic approaches to control or prevent chronic inflammation.



Th17, IgA, microbiota, colitis