The small intestine lamina propria (LP) DC population is largely comprised of two divergent subtypes;CD103+ DCs with homeostatic/tolerogenic properties and CD103- DCs with inflammatory properties. These observations imply a critical role for delivering antigens to the appropriate LP-DC subtype to guide immune responses toward homeostasis or immunity. Recently it was discovered that goblet cells (GCs) act as a passages to deliver soluble luminal antigens to CD103+ LP-DCs. This discovery suggests that GCs play an important and previously unappreciated role in the induction and maintenance of intestinal immune homeostasis. However, mechanistic details are lacking for how this GC function is regulated and how GC mediated antigen delivery contributes to mucosal immune homeostasis. We observed that cholingeric stimuli induce the goblet cell associated antigen passages (GAPs), and that GCs sensitivity to cholinergic stimuli is regulated by sensing the luminal flora. Moreover in the absence of GCs, the cellular intestinal immune compartment is altered, suggesting that GCs play additional roles in shaping the intestinal immune system. Therefore we hypothesize that GCs play a crucial role shaping intestinal immunity through the recruitment and conditioning of LP-DCs, and by regulating antigen delivery in response to intestinal microbiota to promote homeostasis.
In aim 1 we will evaluate how sensing the luminal microbiota alters GC sensitivity to cholinergic stimuli using in vivo imaging and ex vivo studies on gnotobiotic mice, specific pathogen free mice, and induced mutant mice strains.
In aim 2 we will evaluate the cellular source of acetylycholine inducing GAPs and how it is regulated, using ex vivo approaches and induced mutant mice with cell type specific defects in acetylcholine production.
In aim 3 we will evaluate the role of GCs and GAPs in homeostatic immune responses to luminal protein antigens using regimens to induce and challenge oral tolerance. These studies will also evaluate the role of GCs in recruiting and imprinting LP-DCs. Understandning GAP regulation and the role of GAPs in intestinal immune homeostasis may offer new therapeutic interventions for intestinal inflammatory diseases and avenues to optimize oral vaccines.

Public Health Relevance

Chronic inflammatory diseases of the intestine, such as inflammatory bowel disease, result from uncontrolled immune responses to substances in the intestinal lumen. This study will investigate how delivery of luminal substances to the intestinal immune system is regulated and the consequences of altering this process. These studies may identify new treatments for chronic inflammatory diseases of the intestine and suggest how oral vaccines can be improved.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK097317-02
Application #
8545841
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Hamilton, Frank A
Project Start
2012-09-17
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$319,030
Indirect Cost
$109,142
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Knoop, K A; McDonald, K G; McCrate, S et al. (2015) Microbial sensing by goblet cells controls immune surveillance of luminal antigens in the colon. Mucosal Immunol 8:198-210
Miller, M J; Knoop, K A; Newberry, R D (2014) Mind the GAPs: insights into intestinal epithelial barrier maintenance and luminal antigen delivery. Mucosal Immunol 7:452-4
Knoop, Kathryn A; Miller, Mark J; Newberry, Rodney D (2013) Transepithelial antigen delivery in the small intestine: different paths, different outcomes. Curr Opin Gastroenterol 29:112-8