Topic Area and rationale: Inflammatory bowel disease (IBD) is a chronic immune disease that affects millions of Americans and has significant health and economic burden. Although the etiology of IBD remains unknown, disease pathogenesis is attributed in part to the increased infiltration and aberrant inflammatory responses of effector CD4+ T cells in the intestine lamina propria. Blocking of leukocyte trafficking has proved to be effective therapeutic strategy. However, mechanisms that govern CD4+ T cell migration to the colon have precluded colitis-selective treatment, as colon-specific trafficking molecules are poorly defined. Background & Hypothesis: We recently identified GPR15 as a T cell-expressed colon-specific trafficking receptor that plays a significant role in experimental colitis. We found high expression of GPR15 on colon Th2 cells of ulcerative colitis (UC) patients but is absent in mouse Th2 cells. In contrast to the mouse, human colon Tregs in both IBD and non-IBD patients do not seem to express GPR15. Detailed analysis of GPR15 expression in mouse versus human colon led us to identify species differences in Th2 versus Treg expression that correlated with preferential binding of Th2-associated GATA3 vs. Treg-associated Foxp3 transcription factor binding to human and mouse GPR15 enhancers, respectively. In addition to GPR15 expression on colon Th2 cells of UC, significant proportion of the GPR15+ CD4+ effector T cells in the IBD and non-IBD colons lack Th1 or Th17 cytokine expression. As a result, one of the project's goals is to further characterize the non-Th2 colon GPR15+ CD4+ effector T cells and understand their functional significance. Unlike the GATA3 binding motif, there exist two conserved binding sites for the aryl hydrocarbon receptor (AHR) in the GPR15 enhancer. Thus, our overall goal is to determine regulation of GPR15 and define T cell trafficking molecules in the human colon and compare to the mouse.
In aim 1 we will characterize and define CD4+ T effector cells in the normal and inflamed human colon and test the hypothesis that GPR15+ CD4+ T effector cells represent specialized functional subset(s) in the colon under homeostasis and colitis.
In aim 2 we will determine mechanisms that regulate GPR15 expression in the mouse and human, and test the hypothesis that GPR15 is AHR-regulated protein that plays a role in intestinal trafficking of effector T cells in response to AH ligands.
Under aim 3 we will define dendritic cells that regulate GPR15 expression on CD4+ T effector cells in the colon and test the hypothesis that subset(s) of colon dendritic cells are efficient in priming colon homing CD4+ T effector cells. Significance & Impact: In order to develop new specific therapeutic targets and understand the pathogenesis of IBD/colitis, it is essential to elucidate the cellular mechanisms by which effector T cells gain access to the colon. The short-term impact of understanding colon T cell trafficking will be to define role and regulation of colon specific T cell trafficking receptors. The potential long-term impact is of gret clinical significance, as our studies could lead to development of colon T cell specific targets as potent new IBD therapeutics.

Public Health Relevance

: Inflammatory bowel disease (IBD) affects millions of Americans and common therapies available to treat IBD are limited and rely on generalized immune suppressive treatments that often result in either drug intolerance or ill side effects and significant proportions of IBD patients either do not fully respond or become refractory to currently available treatments. Recently trafficking molecule inhibition has proven to be an effective and intestine-specific therapy, however trafficking to the colon remains poorly understood and studies proposed here can improve our knowledge in disease pathogenesis and offer future colon-specific therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK101119-04
Application #
9613809
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
2016-01-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Ocón, Borja; Pan, Junliang; Dinh, Theresa Thu et al. (2017) A Mucosal and Cutaneous Chemokine Ligand for the Lymphocyte Chemoattractant Receptor GPR15. Front Immunol 8:1111
Habtezion, Aida; Nguyen, Linh P; Hadeiba, Husein et al. (2016) Leukocyte Trafficking to the Small Intestine and Colon. Gastroenterology 150:340-54