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 #
4R01DK097317-05
Application #
9069814
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Perrin, Peter J
Project Start
2012-09-17
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
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, Kathryn A; Newberry, Rodney D (2018) Goblet cells: multifaceted players in immunity at mucosal surfaces. Mucosal Immunol 11:1551-1557
Kulkarni, Devesha H; McDonald, Keely G; Knoop, Kathryn A et al. (2018) Goblet cell associated antigen passages are inhibited during Salmonella typhimurium infection to prevent pathogen dissemination and limit responses to dietary antigens. Mucosal Immunol 11:1103-1113
Bando, Jennifer K; Gilfillan, Susan; Song, Christina et al. (2018) The Tumor Necrosis Factor Superfamily Member RANKL Suppresses Effector Cytokine Production in Group 3 Innate Lymphoid Cells. Immunity 48:1208-1219.e4
Knoop, Kathryn A; Gustafsson, Jenny K; McDonald, Keely G et al. (2017) Microbial antigen encounter during a preweaning interval is critical for tolerance to gut bacteria. Sci Immunol 2:
McDonald, Keely G; Wheeler, Leroy W; McDole, Jeremiah R et al. (2017) CCR6 promotes steady-state mononuclear phagocyte association with the intestinal epithelium, imprinting and immune surveillance. Immunology 152:613-627
Chai, Jiani N; Peng, Yangqing; Rengarajan, Sunaina et al. (2017) Helicobacter species are potent drivers of colonic T cell responses in homeostasis and inflammation. Sci Immunol 2:
Knoop, Kathryn A; Gustafsson, Jenny K; McDonald, Keely G et al. (2017) Antibiotics promote the sampling of luminal antigens and bacteria via colonic goblet cell associated antigen passages. Gut Microbes 8:400-411
Nishi, Hiroshi; Furuhashi, Kazuhiro; Cullere, Xavier et al. (2017) Neutrophil Fc?RIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases. J Clin Invest 127:3810-3826
Geem, Duke; Ngo, Vu; Harusato, Akihito et al. (2016) Contribution of Mesenteric Lymph Nodes and GALT to the Intestinal Foxp3+ Regulatory T-Cell Compartment. Cell Mol Gastroenterol Hepatol 2:274-280
Knoop, Kathryn A; McDonald, Keely G; Kulkarni, Devesha H et al. (2016) Antibiotics promote inflammation through the translocation of native commensal colonic bacteria. Gut 65:1100-9

Showing the most recent 10 out of 14 publications