# Role of TRIF-Dependent TLR Signaling in Intestinal Mucosa

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $437,500

## Abstract

Extensive studies have shown that an aggressive mucosal T cell subset that reacts to intestinal bacteria plays
an important role in the cause of inflammatory bowel disease (IBD). These aggressive T cells are thought to
live long as immune-memory cells in peripheral blood and contribute to the chronicity and the relapse of the
disease. Evidence further suggests that a type of T cells, which flexibly secretes different effector molecules,
contributes to the complex pathogenesis of IBD. Another T cell subset, T follicular helper (Tfh)-like cells,
causes severe colitis in animal models, and is abundantly found in peripheral blood of IBD patients. Because
Tfh-like cells are immune-memory cells with highly flexible secretion of effector molecules and are generated in
the intestine, they may contribute significantly to chronic inflammation in IBD. However, the role of Tfh-like cells
in intestinal inflammation and the regulatory mechanisms of their function in the intestine have yet to be
explored. The objective of this application is to identify the key pathways regulating Tfh-like cell generation and
function in the intestine. We have demonstrated that TIR-domain-containing adapter-inducing interferon-β
(TRIF), a molecule that is activated by encountering bacteria and viruses, plays an important role in
maintaining intestinal homeostasis through direction of T cell activation and function. We have found that TRIF
limits the generation of Tfh-like cells and T cell flexibility of effector molecule secretion in the intestine through
the pathways induced by four key molecules; IFNAR, IL27, STAT1, and STAT3. Impairment of TRIF amplifies
Tfh-like cell generation and plasticity, and increased levels of TRIF results in suppression of Tfh-like number
and flexibility. Genetic studies have identified that the abnormalities in the IFNAR, IL27, STAT1, and STAT3
genes are often found in Crohn's disease (CD) patients. Therefore, through the following three aims, we would
like to address our hypothesis that impairment of the TRIF-mediated pathways allows increased generation of
functionally flexible Tfh-like cells that contribute to chronic inflammation in CD, particularly in patients with
genetic variants in the IL27, IFNAR, STAT1, and STAT3 genes. Our specific aims are: (1). Determine the
mechanism by which Tfh-like cells perpetuate destructive inflammation in the intestine. (2). Determine the
mechanisms by which TRIF regulates pathogenic Tfh-like cell generation. (3). Determine the functional
consequence of genetic variants within TRIF-mediated pathways in the generation of pathogenic Tfh-like cells
in patients with CD. Understanding target pathways affecting the generation of highly aggressive T cells may
suggest novel approaches, such as precision medicine, in the management of the subsets of IBD patients in
which inflammation is caused by these T cells. The outcome of this project will be novel insight into the
essential regulatory mechanisms of highly aggressiv...

## Key facts

- **NIH application ID:** 9971345
- **Project number:** 5R01AI095255-08
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Stephan R. Targan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,500
- **Award type:** 5
- **Project period:** 2012-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971345

## Citation

> US National Institutes of Health, RePORTER application 9971345, Role of TRIF-Dependent TLR Signaling in Intestinal Mucosa (5R01AI095255-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971345. Licensed CC0.

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