Role of IL-15 and IL-23 in colitis

Seattle Children'S Hospital, Seattle WA

Investigators

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Abstract

Abstract Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis represent aberrant or dysregulated immune responses of the gastrointestinal tract, which lead to a state of chronic inflammation. Recent discoveries have linked the gene encoding for interleukin-23 (IL-23) receptor with the development of Crohn's, and it is believed that IL-23 has a much larger effect on these inflammatory diseases, as well as affecting risk for both Crohn's and colitis. However, how IL-23 initiates intestinal inflammation remains unclear. Recent data have suggested that the pathogenic role of IL-23 is not only associated with its important role in expanding Th17 cells, but also in driving inflammation mediated by non-T cells. This subset of innate cells that responds to IL-23 and mediates colitis was identified both in mice and in humans, as a subset: group 3 innate lymphoid cells (ILC3) that express the transcriptional factor ROR?t. To determine whether the subsets of ILC3s that promote protective immunity infection are the same as the ones that promote colitis, we used mouse strains that lack certain subsets of ILC3s and evaluated their susceptibility to infection and to develop colitis. Our results suggested that the population of ILC3s that promotes protective immunity is absent in mice that lack the transcriptional factor AHR, whereas the subset of ILC3s that initiate colitis does not require AHR for its function or development. To identify which ones of ILCs promote colitis and the mechanisms by which these cells drive intestinal inflammation, we have generated a triple reporter mouse in which ILC3s that express the transcriptional ROR?t, IL-17 and IFN-g can be tracked in vivo. We believe that this novel cytokine reporter mouse will help us better understand the key role of ILC3s in the development of inflammatory diseases. These studies are needed before we can envision targeting these innate cells for therapeutic benefits.