# Cellular mechanisms by which exhausted T cell responses are restored

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $409,750

## Abstract

Project Summary
T cell responses are continually regulated in quality and magnitude in order to meet the changing requirements
during immune challenge with commensals and infectious organisms. On specific form of adaptation is called T
cell exhaustion and occurs when the source of a non-self antigen cannot be eliminated, such as during chronic
viral infections or in cancer. An exhausted T cell response exerts residual control over pathogen replication or
malignant growth, while at the same time minimizing the immunopathological consequences of ongoing
immune activation. At the level of the individual T cell, exhaustion is characterized by gene expression
programs that facilitate attenuation of T cell receptor signal strength at multiple levels, including the expression
of co-inhibitory receptors, such as PD-1.
In settings where reinvigoration of exhausted T cell responses is desirable, this can in many cases be achieved
by interrupting the PD-1 inhibitory pathway through use of blocking antibodies against PD-1 or its ligand PD-
L1. However, it is not known how reinvigoration of the response occurs at the single cell level and what cellular
interactions and signals govern this process as compared to the priming of naïve or the re-activation of
memory T cells. Can PD-1 blockade instantaneously release the effector activities of exhausted T cells, or
does it initiate a gradual re-differentiation into fully competent effector cells? Are all or only subpopulations of
exhausted cells capable of recovery? Does PD-1 blockade merely prevent exhaustion in cells that are de novo
recruited to the response? What are the requirements for co-stimulation and interaction with specialized
dendritic cells?
To address such questions we have developed a mouse tumor model that allows us to track the response of
individual exhausted T cells to PD-1 pathway blockade at high temporal and spatial resolution using
multiphoton intravital microscopy in tumor tissue. The use of functional fluorescent reporter systems allow us to
monitor TCR-dependent signaling activity in T cells in addition to their effects on local antigen-presenting cells
as well as tumor cells, in order to map the kinetics and heterogeneity of recovery of T cell function upon
binding of blocking anti-PD-1 antibodies. Using this imaging approach in combination with genetic models, we
will also examine the role of local co-stimulation and tumor-associated dendritic cells in restoring the function of
exhausted tumor-infiltrating T cells.

## Key facts

- **NIH application ID:** 9878063
- **Project number:** 5R01AI123349-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Thorsten Roman Mempel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,750
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878063

## Citation

> US National Institutes of Health, RePORTER application 9878063, Cellular mechanisms by which exhausted T cell responses are restored (5R01AI123349-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9878063. Licensed CC0.

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