# Innate T cells learn to find their activating ligands in the skin during their thymic education using cholesterol byproducts

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $209,375

## Abstract

Innate T cells learn to find their activating ligands in the skin during their
thymic education using cholesterol byproducts
Summary
Aberrant skin inflammatory disorder such as atopic dermatitis (AD) is a rampant disease
among children of developed countries, with as many as a quarter of them afflicted. AD
is known to be a disease of allergic T cells that manifest when the skin barrier becomes
degraded. There has been progress in identifying genes involved in tissue barrier
fortification. People with mutations in these genes are predisposed towards allergic
diseases mediated by lymphocytes, but most individuals with genetic susceptibility still
do not develop the diseases, suggesting that there exist immune mechanisms to dampen
harmful inflammatory responses. We discovered that an absence of dermal innate T
lymphocytes programmed to secrete IL-17 and IL-22 results in spontaneous AD in mice
with all major hallmarks of human AD, placing these cells called Tγδ17 as the apex
regulator of skin homeostasis. Murine dermal Tγδ17 cells develop only during neonatal
stages and they are made in the thymus so that they can respond fast when they seed the
skin. However, how these skin regulatory cells localize to the dermis is not known. In this
project we will test the hypothesis that developing Tγδ17 cells learn to localize in the
relevant skin sites in the thymus. This thymic education occurs by restricting maturation
of Tγδ17 thymocytes that can sense cholesterol byproducts oxysterols via the G protein
coupled receptor (GPCR) GPR183 (Ebi2) and/or the CCR6 chemokine receptor ligand
CCL20. In non-inflammatory settings, such as in healthy neonates, GPR183+CCR6+
Tγδ17 cells exit the thymus and enter the skin using CCR6 and then fine-localize in the
dermis using the putative oxysterol gradient. This is a high risk and high reward project,
designed to establish the critical importance of oxysterols for innate T cell positioning in
the body. The conceptual basis is unique as there are no precedents for the GPCR-
dependent maturation of lymphocytes in the tissues of origin that are intimately linked
to the ability of mature lymphocytes to anticipate the same cues in the tissues of
function. This lack of precedent makes the project risky, but if proven to be accurate will
fundamentally alter our understanding of mucosal innate T cell sensing of
environmental alterations and expand the functional domains of cholesterol and its
byproducts in building and maintaining a healthy immune system, especially in
newborns.

## Key facts

- **NIH application ID:** 9851813
- **Project number:** 5R21AI143225-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Joonsoo Kang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2019-01-21 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851813

## Citation

> US National Institutes of Health, RePORTER application 9851813, Innate T cells learn to find their activating ligands in the skin during their thymic education using cholesterol byproducts (5R21AI143225-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9851813. Licensed CC0.

---

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