# Tfh cells:  linking the gut microbiota to a gut-distal autoimmune disease

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2021 · $480,186

## Abstract

PROJECT SUMMARY. Dysbiosis (gut microbiota imbalance) has been implicated in gut-distal autoimmune
diseases, such as autoimmune arthritis and lupus.!However, the mechanisms by which gut microbiota impact
gut-distal/systemic diseases remain largely unknown. T follicular helper (Tfh) cells specialize in helping B cells,
and excessive Tfh responses put patients at risk for autoimmunity. Previously, using the K/BxN autoimmune
arthritis model, we showed that gut commensal segmented filamentous bacteria (SFB) induce arthritis by
driving differentiation and egression of Peyer's patch (PP) Tfh cells into systemic sites, boosting systemic Tfh
responses and exacerbating arthritis. SFB induce PP Tfh differentiation by limiting IL-2 access to CD4+ T cells,
thereby enhancing Bcl-6, the Tfh cell master regulator, in a dendritic cell (DC)-dependent manner. Notably,
many autoimmune patients exhibit IL-2 deficiency, and low-dose IL-2 provides promising autoimmune therapy.
We will determine how microbiota-mediated IL-2 deficiency affects both Tfh-related autoimmunity and IL-2
therapy (Aim 1). We will first examine whether Tfh cell induction by SFB relies on CD25-expressing DCs,
quenching IL-2 secreted by CD4+ T cells at the T-B cell border. We will track single cell migration between gut
and systemic sites and identify circulating Tfh cells as well as peripheral helper T (Tph) cells, a new cell type
found in RA that also helps B cells, in blood as a potential biomarker for dysbiosis-induced autoimmunity in our
mouse model and patients with rheumatoid arthritis (RA). We reported that SFB promote K/BxN autoimmunity
by inducing dual TCR-expressing Th17 cells. Our new data also show the presence of IL-17+ Tfh-like cells in
SFB+ K/BxN mice. We hypothesize that microbiota promote the conversion of Th17 into Tfh cells in PPs,
which enhances autoimmune arthritis (Aim 2). We will examine plasticity by Th17 fate mapping and use single
cell TCR analysis to analyze if a microbiota-skewed dual TCR repertoire promotes autoimmunity. We will use
the Cre-loxP system to address the function of Th17-derived Tfh cells. Chronic antigen (Ag) exposure causes
T cell exhaustion. Autoimmune T cells also encounter chronic Ag, but the role of exhaustion in autoimmunity is
less clear. Prolonged IL-2 exposure induces Blimp-1 and depletes cellular glucose to promote T cell
exhaustion, which is countered by Bcl-6. As SFB reduce IL-2 signaling and induce Bcl-6, we theorize that
microbiota trigger autoimmunity by inhibiting T and/or Tfh cell exhaustion (Aim 3). We will ablate exhaustion
marker Tim-3 to study exhaustion's contribution to autoimmunity. We will examine if IL-2 and microbiota
inversely control Tfh glycolysis to modulate T cell exhaustion. We will also test if gut-derived Tfh and Tph cells
are less exhausted and have increased cellular glucose in human RA. In conclusion, we will learn how
microbiota induce gut-distal diseases by altering gut Tfh cell plasticity and exhaustion. We expec...

## Key facts

- **NIH application ID:** 10090554
- **Project number:** 5R01AI107117-08
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Hsin-Jung Joyce Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $480,186
- **Award type:** 5
- **Project period:** 2013-08-01 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10090554

## Citation

> US National Institutes of Health, RePORTER application 10090554, Tfh cells:  linking the gut microbiota to a gut-distal autoimmune disease (5R01AI107117-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10090554. Licensed CC0.

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