# Inflammation-driven T Cell Responses and their Dichotomous Effect on Host Immunity

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $440,000

## Abstract

PROJECT SUMMARY / ABSTRACT
The memory CD8 T cell compartment can be activated by inflammatory cues even in the absence of a T cell
receptor signal. This process is referred to as bystander-activation of memory T cells and has been observed
following different infections. The contribution of these cells to host immunity was poorly understood until we
recently reported that bystander-activated memory CD8 T cells play a crucial role in controlling early pathogen
replication following infection. We demonstrated that bystander-activated memory CD8 T cells express
granzyme B and can directly kill target cells in a TCR-independent, innate-like fashion. In stark contrast to their
beneficial effect for host immunity following infection, our most recent data provide strong evidence that these
bystander-activated T cells decrease antigen availability following vaccination by eliminating antigen-
presenting cells.
We propose to test the hypothesis that bystander-activated memory CD8 T cells play a fundamental and thus
far unappreciated role in directly controlling the size of the cellular and humoral immune response following
vaccination. We will determine which memory T cell subsets are capable of becoming bystander-activated,
identify how bystander-activated T cells affect subsequent adaptive immune responses and define the
mechanisms that lead to decreased antigen availability following vaccination. We will use a mouse model
system to define the underlying mechanisms of target cell elimination and primary human T cells ex vivo to
ensure direct relevance for human health.
This proposal is highly significant because addressing the role of bystander-activated memory T cells in a
vaccine context is one of the most significant and pressing cellular immunology research topics due to the inability
to achieve effective immunity by vaccination in select populations at risk for and most susceptible to infections.
This proposal is highly innovative because we identified NKG2D as a key molecule in this process and
engineered a novel antagonist designed to enhance vaccine efficacy by inhibiting bystander-activated CD8 T
cell function. Our proposed experiments clearly define the impact of bystander-activation on subsequent
immune responses and to provide a new strategy for enhancing vaccine efficacy.

## Key facts

- **NIH application ID:** 9823846
- **Project number:** 5R01AI123323-04
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Martin Prlic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $440,000
- **Award type:** 5
- **Project period:** 2016-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9823846

## Citation

> US National Institutes of Health, RePORTER application 9823846, Inflammation-driven T Cell Responses and their Dichotomous Effect on Host Immunity (5R01AI123323-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9823846. Licensed CC0.

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