# Notch Regulation of Hematopoietic Cell Fates

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $462,310

## Abstract

T cells are pivotal players in the adaptive immune response. However, when continuously
exposed to antigen, as in persistent infection or cancer, T cells lose effector function and
ultimately become exhausted, leading to chronic infection or progressive disease. Recent
therapeutic advances are based on reversing these natural mechanisms set in place to “quiet”
activated T cells during the resolution phase of an immune response, and in doing so,
reinvigorate immune responses crippled by T cell exhaustion. However, response rates remain
low in many settings; thus, additional strategies are needed. Crucial for developing such
strategies is to identify new targetable pathways, which is currently hampered by our limited
basic knowledge of the negative regulatory pathways that inhibit T cell activation.
 We recently discovered that the pseudokinase Trib1 is a novel negative regulator of T cell
activation, which is induced upon T cell receptor (TCR) stimulation. Our overall goal is to
determine the cellular and molecular mechanisms by which Trib1 regulates T cell responses.
Our preliminary data generated both in vitro and in vivo suggest that in the absence of Trib1, T
cells are hyper-activated and are better able to control chronic infections. Mechanistically, Trib1
appears to exert its effects on T cells via a novel mechanism of regulating NF-κB. Based on
these preliminary data, our overarching hypothesis is that Trib1 suppresses signaling pathways
that promote T cell activation and promotes immune cell exhaustion by limiting T cell effector
function and B cell help. This hypothesis will be tested in two aims: Aim 1 will define the cellular
responses regulated by Trib1, and Aim 2 will determine the signaling pathways responsible for
these findings. Our findings may lead to new insights into controlling T cell activation and
exhaustion in multiple scenarios, including chronic infections and cancer, and in doing so,
identify new avenues for therapeutic interventions.

## Key facts

- **NIH application ID:** 10087845
- **Project number:** 5R01AI047833-19
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MARTHA S JORDAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $462,310
- **Award type:** 5
- **Project period:** 2000-08-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10087845

## Citation

> US National Institutes of Health, RePORTER application 10087845, Notch Regulation of Hematopoietic Cell Fates (5R01AI047833-19). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10087845. Licensed CC0.

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