# Studying the significance of memory CD8+ T cells differentially expressing IL-7 receptor alpha in human aging

> **NIH NIH RF1** · YALE UNIVERSITY · 2024 · $1,858,732

## Abstract

Project Summary/Abstract: Age-associated changes in different elements of the immune system, including
cells, organs and circulating factors, are reported. A meta-analysis on genome-wide transcriptional analyses of
peripheral blood (PB) from ~15,000 people identified 1,497 differentially expressed genes (DEGs) associated
with chronological age. However, contributions of individual immune cells in PB to these changes are not yet
well defined. In human immunity, one of the most prominent changes with age is peripheral memory CD8+ T
cell expansion. We found two distinct cell populations which expressed high and low levels of the T cell
homeostasis cytokine IL-7 receptor alpha chain (CD127 or IL-7Rαhigh and low) in effector memory (EM) CD8+ T
cells in human PB. Compared to young adults (YA, age ≤ 40), older adults (OA, age ≥ 65) had an expansion of
IL-7Rαlow EM CD8+ T cells (up to 70% of total CD8+ T cells) which are highly cytotoxic and inflammatory cells
with unique transcriptome and DNA methylome. About 31% of DEGs (231/744 genes) in IL-7Rαlow EM CD8+ T
cells, in comparison to IL-7Rαhigh EM CD8+ T cells, corresponds to 15.4% of the age-associated genes
(231/1,497 genes, referred to IL-7Rαlow aging genes) found in the above meta-analysis, suggesting the
implication of IL-7Rαlow EM CD8+ T cell expansion in changing the genomic profile of PB with age. Indeed, an
independent group reported the significance of the IL7R gene as an aging biomarker. Aging is the strongest
risk factor for Alzheimer’s disease (AD) that accounts for 60-70% of all dementia. A recent study reported the
expansion of CD45RA+ EM CD8+ T cells in PB and cerebrospinal fluid of AD patients, correlating with
cognition. Importantly, such cells are mostly IL-7Rαlow cells. Of interest, we found that IL-7Rαlow aging genes
and previously reported genes with altered expression in PB of AD patients overlapped. Also, AD patients with
dementia were be divided into 3 subgroups with distinct expression levels of a set of genes, including IL-7Rαlow
aging genes, in PB which were associated with neuropsychological performance. These findings support the
possible implication of IL-7Rαlow EM CD8+ T cells and the IL-7Rαlow aging gene signature in AD although the
clinical and biological significance of such findings is yet to be elucidated. Based on these points, we will
investigate the significance and mechanism of the age-associated expansion of IL-7Rαlow EM CD8+ T cells and
related gene signature in healthy aging and AD with the overarching hypothesis that aging alters transcriptome
and methylome of IL-7Rαlow EM CD8+ T cells, leading to promoting inflammation. The goal of the proposal is to
test this hypothesis with: Aim 1. Investigate whether aging alters global transcriptomic landscape of IL-7Rαlow
EM CD8+ T cells in association with altered DNA methylation, leading to functional changes; Aim 2. Investigate
the significance of IL-7Rαlow EM CD8+ T cell signature in defining subgroups of Alzheimer’s...

## Key facts

- **NIH application ID:** 10890418
- **Project number:** 2RF1AG056728-06
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Insoo Kang
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,858,732
- **Award type:** 2
- **Project period:** 2018-08-15 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890418

## Citation

> US National Institutes of Health, RePORTER application 10890418, Studying the significance of memory CD8+ T cells differentially expressing IL-7 receptor alpha in human aging (2RF1AG056728-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10890418. Licensed CC0.

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