IL-15 is a cytokine critically involved in the pathogenesis of celiac disease (CeD), a T cell-mediated intestinal disorder induced by dietary gluten. In CeD, IL-15 upregulation in intestinal epithelial cells (IECs) is critical for the development of villous atrophy by inducing lymphokine killer activity in cytotoxic intraepithelial lymphocytes (IE-CTL), promoting their survival and expansion, and rendering them resistant to regulation by TGF-?. Furthermore, dysbiosis of the intestinal microbiota has been implicated in CeD pathogenesis, however how it contributes to disease has not been established. Importantly, it is thought that around 40% of adult CeD patients have a partial response to gluten-free diet and do not exhibit the restoration of normal mucosal architecture, and 5-10% of adult CeD patients develop cryptic or overt T cell lymphoma. Our central hypothesis is that overexpression of IL-15 in IECs as found in CeD promotes immunopathology because of its ability to upregulate histone deacetylase (HDAC) activity in IE-CTLs, which cannot be countered by butyrate producing microbiota because of the concomitant development of dysbiosis. The objective of this application is to determine how IL-15 can induce such a comprehensive pathogenic reprogramming of IE-CTLs. The rationale for this project is that its successful completion will provide unprecedented insight into the mechanisms by which dysbiosis contributes to the pathology and the molecular control of IL-15-induced immunopathology, and the understanding of how particular HDAC isoforms control the epigenetic landscape of IE-CTLs. The two aims are synergistic but independent, employing the complementary advantages of studies in human and mouse, respectively. The proposed hypothesis will be tested by pursuing the following specific aims: 1) Characterizing the role of HDAC in the transcriptional and functional programs directed by IL-15 and inflammatory CeD mucosa in IE-CTL. 2) Characterizing the interplay between IL-15 and the microbiota on the reprogramming of IE-CTLs. The proposed research is innovative because it employs cutting-edge genome-wide approaches to reveal novel molecular mechanisms controlling IL-15 induced effector program and epigenetic modifications in IE-CTL. Its scope is wide-ranging because IL-15 is also thought to play a critical role in inflammatory bowel disease, organ-specific autoimmunity, large granular lymphocytic leukemia and enteropathy-associated T cell lymphoma. It will have a significant positive impact on human health because it will help define prophylactic and curative strategies that have the potential to reverse the pathogenic effects of IL-15.
The proposed research will provide a molecular understanding of the mechanisms that control the activation of resident cytolytic T cells that mediate tissue destruction, and the role of the intestinal microbiota in celiac disease pathogenesis. It will have a significant positive impact on human health because it will help define prophylactic and curative strategies that have the potential to reverse the pathogenic effects of IL-15, not only in celiac disease, but also in other IL-15 mediated pathologies such as type-1 diabetes and cytotoxic T cell lymphomas. Thus, this work will directly support the NIDDK mission of developing fundamental knowledge that will help reduce the burden of human disease, and improve the health of patients with digestive disease and type-1 diabetes.
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