?? intraepithelial lymphocytes (IELs) are located within the intestinal epithelial monolayer, either in contact with the epithelial basal surface along the basement membrane, or in the lateral intercellular space between epithelial cells and below the tight junction. ?? IELs have been shown to prevent or exacerbate intestinal disease depending on the context, but ?? IEL behavior and interactions with other cell types in the intestinal mucosa are largely undefined. Until now, ?? IELs were presumed to be sessile, yet my preliminary data demonstrate that ?? IELs exhibit dynamic migratory behavior resulting in extensive interactions with the epithelium. Furthermore, I have shown that ?? IEL motility is dependent upon epithelial and ?? IEL expression of the tight junction protein occludin, and that certain cytokines alter this dynamic migratory behavior both in vitro and in vivo. Together, these observations have led to the central hypothesis that disruption of mucosal homeostasis adversely affects occludin-dependent ?? IEL migration leading to the exacerbation of disease.
The aims of this application are to 1) elucidate the molecular mechanisms by which ?? IELs and epithelial cells interact during ?? IEL migration, 2) determine the effect of ?? IEL migration in IL-15 mediated small intestinal disease and 3) determine how ?? IEL migration contributes to the protection or exacerbation of colitis. A combination of in vivo confocal microscopy, traditional mucosal immunology, and epithelial cell biology techniques will be used to provide new mechanistic insights into the contribution of ?? IEL migration and subsequent epithelial interactions during disease. Moreover, these studies will enhance our understanding of how ?? IELs function within the mucosal microenvironment to regulate health and disease development, and may ultimately lead to new therapeutic approaches designed to modulate ?? IEL motility as means to treat intestinal inflammation. These studies are the first step toward achievement of my long-term goal to identify epithelial/immune cell interactions and determine the relevance of these interactions to IBD and celiac disease. The proposed research and career development plan, along with my mentors, advisory committee and the interdisciplinary approaches encouraged at the University of Chicago, will provide the support and additional training necessary to become an independent investigator in an academic research environment.

Public Health Relevance

?? intraepithelial lymphocytes (IELs) are involved in the regulation of the mucosal microenvironment in several gastrointestinal and autoimmune diseases. These proposed studies will provide new mechanistic insights into how ?? IELs interact with the intestinal epithelium during homeostasis and disease pathogenesis, leading to the development of new therapeutic approaches to improve human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK093627-06
Application #
9206995
Study Section
Special Emphasis Panel (ZDK1-GRB-2 (O1))
Program Officer
Saslowsky, David E
Project Start
2012-02-15
Project End
2017-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
6
Fiscal Year
2016
Total Cost
$163,498
Indirect Cost
$12,111
Name
Rutgers University
Department
Pathology
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
Hu, Madeleine D; Ethridge, Alexander D; Lipstein, Rebecca et al. (2018) Epithelial IL-15 Is a Critical Regulator of ?? Intraepithelial Lymphocyte Motility within the Intestinal Mucosa. J Immunol 201:747-756
Hu, Madeleine D; Jia, Luo; Edelblum, Karen L (2018) Policing the intestinal epithelial barrier: Innate immune functions of intraepithelial lymphocytes. Curr Pathobiol Rep 6:35-46
Edelblum, Karen L; Sharon, Gil; Singh, Gurminder et al. (2017) The Microbiome Activates CD4 T-cell-mediated Immunity to Compensate for Increased Intestinal Permeability. Cell Mol Gastroenterol Hepatol 4:285-297
Hu, Madeleine D; Edelblum, Karen L (2017) Sentinels at the frontline: the role of intraepithelial lymphocytes in inflammatory bowel disease. Curr Pharmacol Rep 3:321-334
Edelblum, Karen L (2016) Dissecting the Requirement for Secondary Lymphoid Organs in Peripheral Regulatory T-Cell Development. Cell Mol Gastroenterol Hepatol 2:253-254
Edelblum, Karen L; Singh, Gurminder; Odenwald, Matthew A et al. (2015) ?? Intraepithelial Lymphocyte Migration Limits Transepithelial Pathogen Invasion and Systemic Disease in Mice. Gastroenterology 148:1417-26
Nalle, Sam C; Kwak, H Aimee; Edelblum, Karen L et al. (2014) Recipient NK cell inactivation and intestinal barrier loss are required for MHC-matched graft-versus-host disease. Sci Transl Med 6:243ra87
Edelblum, Karen L; Shen, Le; Weber, Christopher R et al. (2012) Dynamic migration of ýýýý intraepithelial lymphocytes requires occludin. Proc Natl Acad Sci U S A 109:7097-102