# Specialization of Innate and Adaptive Immune Cells in Intestinal Barrier Function

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $455,611

## Abstract

PROJECT SUMMARY
Specialization of Innate and Adaptive Immune Cells in Intestinal Barrier Function. Maintenance of
mucosal barrier integrity requires the interplay of innate and adaptive immune cells with the mucosal epithelium.
Interleukin-22 (IL-22) is a cytokine of the IL-10 family that is produced by type 3 immune cells, such as group 3
innate lymphoid cells (ILC3s) and cells of the Th17 pathway, and acts on epithelial cells of barrier tissues to
prevent invasion of certain microbes, particularly extracellular bacteria and fungi. The basis for the protective
actions of IL-22 on intestinal epithelial cells (IECs) is not fully understood, but it enhances their production of
antimicrobial factors, maintains epithelial tight junctions and promotes the proliferation and survival of IECs.
Like many immune cytokines that participate in host defense, IL-22 is upregulated in chronic immune-mediated
diseases, and it appears to play a protective role in inflammatory bowel disease (IBD), perhaps by restraining
the epithelial damage caused by dysregulated T cell responses against constituents of the intestinal
microbiome. However, the hyperproliferative effects of IL-22 have also been implicated in epithelial malignant
transformation that leads to colorectal cancer (CRC). We and others have shown that during infectious colitis
modeled by the enteropathogen, C. rodentium, two phases of IL-22 production can be distinguished: an early
phase dominated by IL-22–producing innate immune cells, and a late phase that is dominated by IL-22–
producing CD4 T cells. While both innate and adaptive immune cells produce IL-22 during infection, their
relative contributions to host protection are unknown, as are details of the mechanisms by which IL-22 acts. In
preliminary studies, we have generated novel IL-22 reporter/conditional knockout (cKO) mice with which to
track and/or delete specific subsets of IL-22-producing immune cells. Remarkably, we find that the locations
and functions of IL-22–producing cells during C. rodentium infection are distinct: innate immune cells,
dominated by ILC3s, localize primarily to isolated lymphoid follicles and activate superficial IECs at initial sites
of bacterial colonization. However, ILC3s fail to protect the intestinal crypts, which are invaded by bacteria in
mice with IL-22 deficiency targeted to T cells. Thus, IL-22–producing T cells appear to be indispensible for
protection of the intestinal crypts via their activation of crypt-lining epithelium. We hypothesize that IL-22–
producing innate cells are limited to rapid activation of superficial IECs at initial sites of bacterial attachment,
whereas IL-22–producing T cells are required to prevent bacterial invasion of crypts. Moreover, superficial and
crypt IECs differ in their response to IL-22-dependent innate and adaptive signals. In this proposal we will
define the relative contributions of innate and adaptive immune cells to IL-22–dependent activation of different
subsets of col...

## Key facts

- **NIH application ID:** 9879737
- **Project number:** 5R01DK113789-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Casey T Weaver
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $455,611
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879737

## Citation

> US National Institutes of Health, RePORTER application 9879737, Specialization of Innate and Adaptive Immune Cells in Intestinal Barrier Function (5R01DK113789-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9879737. Licensed CC0.

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