# Hippo signaling in stable regulatory activity and immune tolerance

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $448,750

## Abstract

Program Description/Abstract
A central component of peripheral immune tolerance is Foxp3[+] regulatory T cells (Tregs). Tregs are indispensable for the prevention of autoimmune diseases, but also serve as a major hurdle to tumor immunity and immunotherapy. IL-2 is considered a major regulator for controlling the homeostasis and more recently, lineage stability, of Tregs by signaling through STAT5. Recent studies have also discovered a highly suppressive p-STAT5[+] Treg subpopulation that is critical for the suppression of autoreactive T cells and incipient autoimmunity. Of note, low-dose IL-2 specifically activates Tregs to ameliorate autoimmune diseases in murine models and clinical trials, and there is a growing interest in exploring this new therapeutic strategy. Unlike conventional T cells, Tregs are normally kept in a state of partial IL-2 deficiency due to, in part, Foxp3-dependent repression of IL-2 production and are therefore indexed to a low IL-2 signaling threshold. Additionally, Tregs show a predominant requirement of STAT5 activity due to their low PI3K and MAPK activities downstream of IL-2R. Mechanisms underlying Treg-specific regulation of IL-2 and STAT5 signaling remain uncertain. Through a kinase inhibitor screen, we identified Mst1, a core kinase in Hippo signaling, as a novel IL-2 signal sensor to amplify STAT5 activation in Tregs but not conventional T cells. We therefore hypothesize that Hippo kinases selectively sense and amplify IL-2R−STAT5 signaling to adapt Tregs to a proper IL-2 signaling threshold, thereby maintaining a stable Treg population and regulatory activity. Aim 1. Establish Mst1−STAT5 axis in Tregs under homeostasis and activation in vivo. Aim 2. How does Hippo/Mst1 signal in Tregs? Aim 3. Define and reconstruct IL-2-dependent signaling circuits in Tregs. We predict our studies will establish a new paradigm in Treg biology and immune regulation, as well as new mechanisms of Hippo signaling, with the potential to translate into innovative strategies to target autoimmunity and cancer.

## Key facts

- **NIH application ID:** 9960431
- **Project number:** 5R01AI140761-03
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Hongbo Chi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $448,750
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960431

## Citation

> US National Institutes of Health, RePORTER application 9960431, Hippo signaling in stable regulatory activity and immune tolerance (5R01AI140761-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9960431. Licensed CC0.

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