Characterization of E. coli-specific T cells in Crohn's disease

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PROJECT SUMMARY/ABSTRACT Several lines of evidence have implicated T cells in the pathogenesis of Crohn's disease, an uncontrolled inflammatory condition of the intestines in which immune cells overreact to the bacteria that live there. Previous studies of antigen-nonspecific T cells in Crohn's disease have not identified overall differences in them that would explain this over reactivity. However, we have recently identified CD4 T cells of the immune system that can react to a peptide from protein antigen (OmpC) made by one such bacteria (E. coli), to which antibodies are commonly seen only in people with Crohn's disease. We found that these OmpC-specific cells make IL-10 unless they come from Crohn's disease patients, and hypothesize that this defect plays a central role in the inflammation of Crohn's disease. IL-10 is a cytokine that clearly plays a central role in limiting inflammation in the intestines, because mice without the IL-10 gene and humans born with a mutation in the receptor for IL-10 both quickly develop severe enterocolitis, resembling Crohn's disease. The overall goal of the studies proposed here is to determine why these gut flora antigen-specific T cells fail to make IL-10 in Crohn's disease, as a mechanism by which tolerance to gut flora is lost in this condition. The novel approach is to integrate single cell gene expression and epigenetic analyses in these OmpC-specific T cells we can isolate with MHC-II tetramers. The hypothesis will be addressed in two Specific Aims with genome-wide expression differences correlated with IL-10 expression in Aim 1, and an epigenetic basis for failed IL-10 expression in Crohn's disease to be revealed in Aim 2. Together these studies will advance our understanding of abnormal IL-10 regulation by gut microbial antigen-specific T cells in Crohn's disease, and provide the foundation for determining how such a defect contributes to disease pathogenesis.