# TGF-b superfamily signaling in controlling Th17 cell function in autoimmune neuroinflammation

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $383,176

## Abstract

Project Summary:
 Multiple sclerosis (MS) is a debilitating autoimmune neuroinflammation disease inflicting millions of
people worldwide. It is caused by dysregulated adaptive and innate immunity. CD4 T cells critically contribute
to MS development in humans and EAE development in mice. Particularly, Th17 cells are central to
autoimmune neuroinflammation. To understand the etiology of and develop treatment for MS, one of the main
goals of MS research is to understand how T cell and Th17 cell function are controlled. Transforming growth
factor–β (TGF-β) is instrumental in Th17 cell differentiation and function. Yet it is unclear whether and how
TGF-β superfamily member other than TGF-β controls Th17 cell differentiation in MS/EAE.
 Our recent findings revealed novel TGF-β superfamily and related signaling to regulate Th17 cell
function and the development of autoimmune neuroinflammation: (1) SKI protein, a TGF-β signaling
suppressor that is degraded upon TGF-β stimulation, suppresses Th17 cell differentiation in vitro and in vivo,
(2) SKI expression in T cells completely protected mice from EAE, (3) Activin-A, a TGF-β superfamily member
that is closely related to TGF-β, was upregulated during EAE and in activated T cells in inflamed tissues and in
the presence of proinflammatory cytokines, and (4) Activin-A+IL6 induced SKI degradation and the
differentiation of Th17 cells that phenotypically resemble pathogenic- rather than non-pathogenic-Th17 cells to
promote EAE. We therefore hypothesize that TGF-β superfamily member Activin-A is a novel factor distinct
from TGF-β to promote pathogenic Th17 function and autoimmune neuroinflammation through SKI. In this
study, we proposed to reach the following three Aims. AIM 1: Address whether Activin-A is required for Th17
cell function and EAE. AIM 2: Reveal the molecular program of Activin-A induced Th17 cell generation and
function; AIM 3: Investigate the mechanisms underlying SKI controlled Th17 cell function and EAE.
 There is a great and yet unmet need in the understanding of how Th17 cell function during autoimmune
neuroinflammation. This study aims to reveal previous unappreciated cellular and molecular mechanisms
underlying TGF-β superfamily signaling in controlling Th17 cell differentiation and function for autoimmunity.
The success of this study will gain critical mechanistic insights into T cell mediated autoimmune
neuroinflammation and shed new light on how to mitigate related disease by targeting TGF-β superfamily
signaling pathways.

## Key facts

- **NIH application ID:** 10330037
- **Project number:** 5R01AI160774-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Yisong Wan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $383,176
- **Award type:** 5
- **Project period:** 2021-01-16 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10330037

## Citation

> US National Institutes of Health, RePORTER application 10330037, TGF-b superfamily signaling in controlling Th17 cell function in autoimmune neuroinflammation (5R01AI160774-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10330037. Licensed CC0.

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