# Regulatory mechanisms governing Th17 cell effector identity and plasticity

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $382,149

## Abstract

PROJECT SUMMARY
T helper (Th) cells are CD4-expressing T lymphocytes that diversify into several subclasses to support distinct
immune responses. Among the diversity of Th subset differentiation options, IL-17A-producing inflammatory
Th17 cells stand out as unique by virtue of their relatively high level of inherent plasticity. Indeed, this subset
that normally functions in mucosal immunity against bacteria and fungi can easily adopt features of other T
helper subsets when environmental conditions change. While this feature can be advantageous during the
clearance of an infection, dysregulated Th17 cell function has been implicated in numerous autoimmune
conditions, including Inflammatory Bowel Disease, Multiple Sclerosis, and Rheumatoid Arthritis. Moreover,
Th17 cell plasticity exhibited in the context of inflammatory disease tends to take on Th1-like traits, such as
expression of IFNg or T-bet, that are also associated with increased pathology. In our current funded studies,
we identified a JunB-T-bet axis as a central node in the regulatory network governing Th17 cell lineage stability
versus plasticity. While several regulators influencing the transcriptional program of Th17 cell identity and
flexibility have been identified, less is known about the regulators of the three-dimensional genome architecture
that differs between cell types and states and is a critical determinant of gene regulation. Thus, we hypothesize
that regulation of chromatin confirmation by lineage-specific factors is key to the control of CD4 T cell effector
conversions. Here, we propose to comprehensively evaluate the dynamic changes in chromatin configuration
and the cis genomic elements that govern Th17 cell effector conversions in vivo. To this end, in Aim 1, we will
apply genetic fate-mapping mouse models, global chromatin conformation assays, and epigenomic profiling
tools to characterize the chromatin looping dynamics during Th17 cell plasticity in a mouse model of
experimental autoimmune encephalomyelitis (EAE). We will determine the contribution of looping to Th17 cell
plastic conversion by assessing the role of both chromatin organizing proteins and lineage-regulating
transcription factors. In Aim 2, we plan to determine the cis regulatory network that governs Th17 cell plasticity.
For this, we will apply scATACseq profiling of Th cells in EAE to identify plasticity-associated cis elements. We
will validate candidates for activity and function using novel in vivo high throughput reporter assays and
CRISPR/Cas9 epigenomic screens. This will identify new regulatory networks, regulators, and gene targets
critical to Th17 cell effector plasticity. Taken together, the proposed work will fill an important gap in knowledge
concerning the molecular mechanism governing stability versus plasticity of Th17 cells.

## Key facts

- **NIH application ID:** 10211809
- **Project number:** 2R01GM115474-06
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Maria Ciofani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,149
- **Award type:** 2
- **Project period:** 2016-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10211809

## Citation

> US National Institutes of Health, RePORTER application 10211809, Regulatory mechanisms governing Th17 cell effector identity and plasticity (2R01GM115474-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10211809. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*