# Role of Notch signaling during the early priming and activation of alloreactive T cells

> **NIH NIH F30** · UNIVERSITY OF PENNSYLVANIA · 2021 · $51,036

## Abstract

PROJECT SUMMARY
 Graft-versus-host-disease (GVHD) is the most serious complication of allogeneic bone marrow
transplantation (allo-BMT). GVHD pathogenesis is mediated by alloreactive T cells present in the graft that
recognize alloantigens and damage host tissues. Most GVHD therapies rely on global immunosuppression and
are associated with increased risks of infection and decreased graft-versus-tumor effects. New strategies for
GVHD prevention that protect host tissues while simultaneously preserving the tumor-killing activity of
alloimmune T cells are needed. Our laboratory identified Notch signaling and Delta-like1/4 (Dll1/Dll4) Notch
ligands as critical regulators of the pathogenic allo-T cell response, and attractive new therapeutic targets. In
both mouse and non-human primate models, Notch inhibition in donor T cells leads to long-term protection
from GVHD morbidity and mortality. Short-term in vivo Notch blockade using monoclonal antibodies against
specific Notch receptors or ligands blunts the pathogenicity of alloreactive effector T cells without eliciting
broad immunosuppression, reducing GVT activity, or triggering toxic side effects of chronic Notch inhibition.
While a single injection of anti-Dll1/Dll4 Notch ligand antibodies at the time of transplant was sufficient for long-
term GVHD control, Dll1/Dll4 blockade administered >48 hours after transplant provided no protection against
GVHD. Thus, an early pulse of Notch signaling during the initial stages of T cell activation is critical for
establishing a pathogenic T cell state. However, we do not currently understand how short-term Notch
inhibition exerts long-lasting GVHD protection. Alloreactive T cells rely on two central functions to mediate
disease: trafficking to peripheral target organs and producing proinflammatory cytokines. Our preliminary data
show that Notch inhibition preserves initial T cell IL-2 production and expansion in secondary lymphoid organs
while impairing secretion of multiple inflammatory cytokines and homing to the gastrointestinal tract. Therefore,
I hypothesize that Notch signals delivered to allo-T cells during early stages of T cell priming and activation are
critical for trafficking to the gut and initiating a sustained inflammatory cytokine response. I speculate that these
two key mechanisms explain why short-term Notch inhibition prevents many of the severe, pathological
consequences of GVHD. To explore this hypothesis, I will use MHC-mismatched models of GVHD to
investigate how Notch inhibition influences allo-T cell gut tropism. Moreover, I will use a combination of RNA
sequencing, Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), and Cleave Under
Targets and Release using Nuclease (CUT&RUN) chromatin profiling to provide a genome-wide view of the
transcriptional and epigenetic effects of Notch signaling during early stages of allo-T cell priming/activation.
Altogether, this proposal will elucidate the cellular and molecular mechanis...

## Key facts

- **NIH application ID:** 10232480
- **Project number:** 1F30AI161873-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Ashley Nicole Vanderbeck
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232480

## Citation

> US National Institutes of Health, RePORTER application 10232480, Role of Notch signaling during the early priming and activation of alloreactive T cells (1F30AI161873-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10232480. Licensed CC0.

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