Recent studies identified a subset of NK cells associated with mucosal surfaces, or mucosal NK cells. These NK cells displayed multiple unique properties including the production of IL-22 to promote epithelial repair and homeostasis in response to proinflammatory cytokines, and accordingly these IL-22 producing NK cells have been demonstrated to play an important role in ameliorating intestinal inflammation. These mucosal NK cells are generated in response to inflammation and have an origin distinct from conventional NK cells. Moreover mucosal NK cells have a phenotype resembling the adult lymphoid tissue inducer (LTi) like cells that are responsible for the formation of solitary intestinal lymphoid tissues (SILT), including their developmental dependence upon the transcription factor ROR3t, and their residence within SILT in the uninflamed intestine. Based upon these observations and our preliminary data we hypothesize that during intestinal inflammation adult LTi like cells within the SILT differentiate into mucosal NK cells, subsequently mature in response to IL-21 produced by T-lymphocytes, and redistribute to the inflamed epithelium to produce IL-22 in response to IL-23 to mediate epithelial repair and maintenance.
In specific aim 1 we will evaluate the ability of LTi like cells from the adult intestine to differentiate into mucosal NK cells and dendritic cells (DC) and evaluate the factors promoting mucosal NK cell and DC development.
In specific aim 2 we will identify the role of SILT and luminal microbiota in the process of mucosal NK cell development and mucosal NK cell redistribution to the epithelium.
In specific aim 3 we will evaluate the factors/cell types playing a role in mucosal NK cell maturation, redistribution, and IL-22 production. Findings from these studies will significantly increase our understanding of how the mucosal immune system facilitates epithelial barrier maintenance and repair during inflammation, and will open up new avenues of investigation for treatment of chronic inflammatory diseases of the intestine.

Public Health Relevance

During intestinal inflammation a unique population of natural killer cells are generated. These cells produce cytokines promoting epithelial barrier maintenance and repair in response to inflammatory mediators. This proposal will investigate how these cells are generated and how they function to promote epithelial repair.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064798-09
Application #
8537418
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Carrington, Jill L
Project Start
2005-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
9
Fiscal Year
2013
Total Cost
$301,317
Indirect Cost
$103,082
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Lee, Jacob S; Cella, Marina; McDonald, Keely G et al. (2012) AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat Immunol 13:144-51

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