# Control of regulatory T cell homeostasis and function by Notch signaling

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $442,500

## Abstract

Abstract
Foxp3+ regulatory T (TR) play a requisite role in peripheral immunological tolerance and in restraining
exuberant immune responses. Elucidating mechanisms that control TR cell responses is of pivotal importance
to the restoration of tolerance in diseases of chronic inflammation and autoimmunity. Relevant to this goal is
our recent determination of a critical role for the Notch pathway in regulating the peripheral TR cell
compartment. TR cell-specific deletion of Notch1 antagonized T helper (Th)1 responses and protected against
graft versus host disease, while TR cell-specific constitutive expression of the intracellular domain of Notch1
led to lymphoproliferation, Th1 cell dysregulation and autoimmunity. We have also demonstrated that TR cell-
specific loss of function Notch pathway mutations that incapacitate signaling via all Notch receptors (Pofut1
deletion) or canonical pathway signaling (Rbpj deletion) but not deletion of Notch1 or Notch2, protected against
allergic airway inflammation, indicating that individual Notch receptors on TR cells mediated regulation of
distinct Th cell programs. Some of the effects of Notch signaling in TR cells involved transcriptional activation
via the canonical Notch pathway co-factor RBPJ. Yet others appeared to involve activation of the non-
canonical mechanisms. Accordingly, We hypothesize that Notch signaling fulfills an important physiological
role in negatively regulating TR cells to ensure optimal immune homeostasis. Excessive activation of this
pathway would result in TR cell dysfunction, leading to immune dysregulation, inflammation and autoimmunity.
We further hypothesize that individual Notch receptors on TR cells fulfill non-redundant roles in controlling Th
cell responses, with Notch1 regulating Th1 and Notch4 Th2 cell responses, respectively. We also hypothesize
that the capacity of individual Notch receptors on TR cells to mediate distinct immune regulatory outcomes is
reflected by hierarchal Notch receptor-ligand interactions and by distinct transcriptional circuitries activated by
the respective Notch receptors. We propose under Aim 1 to elucidate mechanisms by which sustained Notch1
signaling in TR cells promotes dysregulated Th1 cell responses by enabling complete Th1 cell reprogramming
of TR cells, and the role of T follicular regulatory (TFR) cell subversion by Notch1 signaling in inciting intense
humoral autoimmunity. Under Aim 2, we will examine mechanisms by which Notch signaling in TR cells, most
notably that by Notch4 (and possibly Notch3), regulates Th2 cell responses in allergic airway inflammation,
while Aim 3 will explore mechanisms by which signaling via different Notch receptors in TR cells leads to
distinct functional outcomes, including ligand specificity of the respective receptor expressed on TR cells and
the nature of the downstream transcriptional programs activated upon Notch1 versus Notch4 signaling. The
proposed studies will identify novel mechanisms by which N...

## Key facts

- **NIH application ID:** 9913447
- **Project number:** 5R01AI115699-04
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Talal Amine Chatila
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $442,500
- **Award type:** 5
- **Project period:** 2017-05-04 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913447

## Citation

> US National Institutes of Health, RePORTER application 9913447, Control of regulatory T cell homeostasis and function by Notch signaling (5R01AI115699-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9913447. Licensed CC0.

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