The body?s largest collection of immune cells underlies the single layer epithelium lining the GI tract and monitors the luminal contents to maintain tolerance to dietary antigens in the steady-state and to induce immunity to pathogens during infection. How the immune system?s exposure to luminal antigens is controlled in the steady-state to promote tolerance and during infection to avoid inappropriate responses and promote immunity remains a significant gap in our understanding. We propose that luminal antigen delivery to the immune system is tightly controlled, has regional variation through the GI tract, and serves to supply antigens to the immune system and guide the phenotype of immune responses. Goblet cells (GCs) can take up luminal substances deliver them to antigen presenting cells in the underlying lamina propria (LP) in a manner capable of inducing adaptive immune responses, in a process termed Goblet cell-associated Antigen Passages (GAPs). GAP formation is induced by acetylcholine acting on GCs, is linked with secretion, and is inhibited by GC intrinsic sensing of the gut microbiota. We propose that the pathways controlling GAP formation and the properties of GAPs in various regions of the GI tract allow for a regional antigen delivery supporting tolerance to dietary antigens in the steady-state and limiting immune responses to innocuous luminal antigens and shifting the phenotype of the immune response during enteric infection. These observations give rise to the overarching hypothesis that GC-mediated antigen delivery occurs via bulk endocytosis (BE) in GCs, is a major and closely regulated mechanism promoting tolerance in the steady-state, and inhibition of this pathway shifts immune responses to promote pathogen clearance and immunity during infection. To explore this hypothesis we propose the following specific aims:
Aim 1 will define the ultrastructural basis and cellular biology of GAP formation using state-of-the-art imaging approaches, and genetic and pharmacologic manipulation of endocytosis and GAPs.
Aim 2 will define the role of GC/GAPs in the induction and maintenance of tolerance to luminal antigens in the steady-state using genetic manipulation of GAP formation.
Aim 3 will define if altering GCs/GAPs results in inappropriate inflammatory responses to dietary antigens and/or worsened outcomes during infection using genetic manipulation of GAPs in Salmonella typhimurium infection.

Public Health Relevance

The intestinal immune system must protect us from a wide array of potential pathogens and simultaneously maintain tolerance to dietary antigens. This study will investigate a novel antigen delivery mechanism that promotes tolerance in the steady-state and alters to avoid inappropriate responses to dietary antigen and promote pathogen clearance during infection. Findings from work performed in this proposal will significantly add to our understanding of how immune responses are regulated to promote health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK097317-07
Application #
9532819
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Perrin, Peter J
Project Start
2012-09-17
Project End
2021-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
7
Fiscal Year
2018
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
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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

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