# Microbiota Control Lung Th17 Cell Response and Plasticity Leading to Autoimmune Lung Disease

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2022 · $455,819

## Abstract

Project Summary.
Lung complications are a common and major cause of death in patients with rheumatoid arthritis (RA).
Therapies are limited, and arthritis modulating drugs can actually worsen lung disease in RA patients, yet little
is known regarding RA-related lung pathogenesis. It is evident that the gut and gut microbiota have a strong
influence in many lung diseases. Mechanistically, this phenomenon known as the gut-lung axis, is poorly
defined. We reported that through gut-lung communication, a gut commensal, segmented filamentous bacteria
(SFB) are able to expand dual T cell receptor (TCR)-expressing T helper 17 (Th17) cells, leading to lung
tertiary lymphoid structures (TLS), lesions often associated with poor prognosis in autoimmune patients. To
understand gut-lung axis, we propose addressing the mechanisms utilized by SFB to promote a Th17 cell
response, gut-lung migration, and lung TLS formation. Hypoxia-inducible factor-1α (HIF-1α) senses O2 in
hypoxic tissues, e.g. the gut and inflamed tissues, and is known to enhance glycolysis and promote Th17 cell
differentiation. Recent studies reported reoxygenation of T cells in tissue culture chambers greatly enhances
HIF-1a induction. Importantly, gut (hypoxic)-derived T cells entering the lung (normoxic) may face similar O2
changes. We hypothesize and will test whether the gut microbiota in combination with lung reoxygenation up-
regulate HIF-1α expression in gut-derived lung CD4+ T cells, promoting their glycolytic activity and Th17 cell
commitment, and worsening lung disease. Using the KikGR-photoconvertible model to trace T cells from gut to
lung, our new data favor our hypothesis by showing a higher HIF-1α level in KikR (gut-derived) than KikG CD4+
T cells in lung but not spleen of SFB+ mice. CCR6 is highly expressed by Th17 cells. Our new data show that
type 2 alveolar epithelial cells (AEC2) produce abundant CCL20, the CCR6 ligand in the pre-autoimmune
disease phase. We will test whether lung microbiota and innate signaling are required for AEC2s’ CCL20
expression and Th17 cell recruitment by using AEC2-specific MyD88 and CCL20 depletions. Recently, gut
microbiota have been shown to locally induce an intriguing gut T cell type co-expressing Rorγt+ and Foxp3+,
master regulators of Th17 cells and Tregs. However, whether and how gut microbiota can remotely regulate T
cell plasticity in the lung remains unknown. Our new data show that a unique population of IL-17+Foxp3+ cells
is significantly increased in lung of SFB+ over SFB− mice. We will examine T cell plasticity by Treg fate
mapping, and use single cell TCR analysis to analyze whether a microbiota-skewed dual TCR repertoire allows
Foxp3+ T cells to acquire a Th17-like phenotype. Finally, we will use the Cre-loxP system to address the “good
or evil” function of IL-17+Foxp3+ T cells in lung autoimmunity. By taking a unique approach of tracking gut-lung
crosstalk, this proposal permits studies to reveal the etiology of gut-lung axis, help...

## Key facts

- **NIH application ID:** 10447594
- **Project number:** 5R01HL148347-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Hsin-Jung Joyce Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $455,819
- **Award type:** 5
- **Project period:** 2020-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447594

## Citation

> US National Institutes of Health, RePORTER application 10447594, Microbiota Control Lung Th17 Cell Response and Plasticity Leading to Autoimmune Lung Disease (5R01HL148347-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10447594. Licensed CC0.

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