# Regulation of memory CD8 T cell development

> **NIH NIH R37** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2022 · $416,957

## Abstract

Abstract
 Alzheimer’s disease (AD) is a complicated disease driven by both genetic and environmental components,
which collectively converge upon inflammation as a common driver 1. Notably, inflammatory insults to the central
nervous system (CNS) such as viral infection are correlated with AD and other forms of cognitive decline 2–4,
although the mechanisms linking prior neuroinflammatory exposure to subsequent AD development
remain unclear. Viral infection leads to profound remodeling of tissues that can have long-term effects on the
composition of immune cells in tissues as well as their inflammatory states. For example, after many forms of
infection, memory T cells that “remember the virus” infiltrate and then persist in the brain long-term as tissue-
resident memory T (TRM) cells 5,6. While TRM cells play key roles in local protection against viral re-infection in
tissues, their presence can also lead to dysregulated and unwanted inflammation 6. Moreover, the brain resident
macrophages, microglia, can be ‘trained’ or functionally reprogrammed after exposure to infection 7, leaving the
cells in a poised state that can more swiftly produce inflammatory mediators upon re-infection. While protective
to re-infection, these poised inflamed states of brain-resident TRM cells and microglia may put the brain at risk of
unwanted, periodic or chronic inflammation. Nearly all AD animal research is performed in animals in specific-
pathogen free (SPF) conditions, protected from exposure to environmentally-relevant microbes or viruses.
Therefore, this project aims to develop more physiological animal models of AD that examine the
influence of successive viral infections on the remodeling of the CNS and brain-resident microglia and
TRM cells, to see if this predisposes the CNS to increased risk of inflammation, tissue stress and hastens
neurodegeneration and AD pathogenesis. To test this idea, we will serially infect mice genetically
predisposed to develop AD-like symptoms with different viruses over the first half of their lifetime (every ~2
months). This will help replicate a more typical exposure to multiple pathogens over one’s lifetime. As the mice
age, we will examine changes in the composition and function of immune cells, astrocytes and neurons, and
look for earlier signs of AD pathology and dementia. This application will test if a history of infection increases
age-related inflammation in the CNS, such as Type I interferons. By defining pathological links between serial
infection, chronic inflammation and brain resident immune cells, these studies will address this gap in knowledge
between one’s infection history and age-related inflammation in the brain that supports AD pathogenesis, and
mechanistically define environmental drivers of sporadic AD. Furthermore, our studies will shed light on the role
of brain TRM cells, and how they regulate the inflammatory tone of the CNS. Considering that AD is an irreversible
pathology that currently lacks any...

## Key facts

- **NIH application ID:** 10499938
- **Project number:** 3R37AI066232-18S1
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Susan M Kaech
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $416,957
- **Award type:** 3
- **Project period:** 2005-05-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499938

## Citation

> US National Institutes of Health, RePORTER application 10499938, Regulation of memory CD8 T cell development (3R37AI066232-18S1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10499938. Licensed CC0.

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