Impact of Aiolos on intestinal intraepithelial lymphocytes

点击翻译按钮获取中文摘要

Project Summary/Abstract Inflammatory bowel disease (IBD) is a common disorder that causes inflammation predominantly in the digestive tract. Although treatment options have expanded in the past two decades, a significant portion of patients still suffer from poor treatment response and chronic clinical courses. Various responses to currently available therapy are in part due to the heterogeneity of pathogenesis, and novel mechanistic insight that could lead to new therapeutic options is critically needed. Intestinal intraepithelial lymphocytes (IELs) are a heterogeneous group of tissue-resident lymphocytes, and pathological activation of IELs is implicated in the exacerbation of IBD. However, the regulatory mechanisms of IELs during activation are not well understood. Aiolos, a transcription factor encoded by Ikzf3, is expressed exclusively in lymphocytes, and contributes to B cell activation and NK cell maturation. Aiolos mutations are implicated in various autoimmune diseases including IBD, but the roles of Aiolos in IELs or gut homeostasis have not been studied in the past. I discovered that Aiolos is highly expressed in IELs and that Aiolos-deficient IELs are more activated and express higher levels of activation markers (NK receptors) and cytokines (interferon-g and granzymes) compared to wild-type cells. These preliminary results indicate that Aiolos strongly suppresses IEL activation. Since Aiolos is a transcription factor modulating chromatin remodeling, I hypothesize that Aiolos binds to the enhancer regions of genes associated with IEL activation and controls their expression by altering epigenetic modifications. Additionally, since Aiolos potently regulates IEL activation, I hypothesize that Aiolos-deficient IELs modulate the host response to colitogenic infection and intestinal inflammation. In this proposed project, I will address these hypotheses with the following aims: (Aim 1) to identify Aiolos binding sites and define the contribution of Aiolos to epigenetic landscape in IELs, and (Aim 2) to investigate the impact of Aiolos-deficient IELs during mucosal inflammation. In Aim 1, I will utilize state-of- the-art epigenetic techniques to examine Aiolos binding sites in wild-type IELs and investigate how Aiolos deficiency alters epigenetic modifications in IELs. I plan to examine differences of epigenetic modifications between Aiolos-deficient IELs and wild-type IELs by comparing open chromatin regions and histone modifications. In Aim 2, I will challenge mice with Aiolos-deficient IELs and mice with wild-type IELs with Salmonella typhimurium and dextran sodium salt-induced colitis to delineate the impact of Aiolos-deficient IELs on host responses to intestinal infection and inflammation. Taken together, this project will contribute to profiling cis-regulatory circuits of IELs and could advance our understanding of the pathogenesis of IBD, which could eventually lead to the identification of new therapeutic targets.