# Understand the molecular mechanism of age-associated decline in antiviral CD8 T cell immunity

> **NIH NIH R21** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $246,000

## Abstract

Summary
Immunosenescence increases morbidity and mortality after infection and reduces vaccine efficacy. Most deaths
associated with infections by influenza virus, SARS-CoV, or SARS-CoV-2 occurred in people older than 65. Thus,
understanding the mechanism of age-associated decline in antiviral immunity is critical to the development of
strategies to protect the elderly from viral pathogens. Despite its critical role in protection against infections, T-
cell immunity declines with age. During aging, the prevalence of naïve T cells decreases, whereas the frequency
of terminally differentiated CD8 T cells increases. In addition, aging reduces the responsiveness of naïve T cells
to antigen. However, the molecular mechanism underlying age-associated decline in antiviral T cell immunity
remains poorly defined. Using a mouse model of murine hepatitis virus (MHV) infection, we found that aging
increased mortality and decreased antiviral CD4 and CD8 T cell responses. Surprisingly, although aging
increased terminally differentiated CD8 T cells at baseline, there was a profound reduction in terminally
differentiated effector CD8 T cells and an elevated gene-signature of T-cell exhaustion in aged mice after MHV
infection. In addition, we showed that age-associated decline in T-cell expansion was primarily caused by TCR-
triggered apoptosis and necroptosis pathways and was rescued by rebalancing TCR and IL2 signaling. We also
found that aging reduced the metabolic rate of T cells at baseline and impaired metabolic adaptation of T cells
after activation. Here, we hypothesize that age-associated exhaustion-prone epigenetic state and defective
metabolic adaptation impair effector CD8 T cell response in viral infection. In this study, we will define the
epigenetic and metabolic pathways in antiviral CD8 T cells altered by aging before and after infection, while
accounting for age-associated changes in differentiation. We will also evaluate strategies that harness IL2 and
TCR pathways to rescue age-related defects in antiviral CD8 T cells.

## Key facts

- **NIH application ID:** 10910173
- **Project number:** 5R21AG083398-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Tuoqi Wu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $246,000
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10910173

## Citation

> US National Institutes of Health, RePORTER application 10910173, Understand the molecular mechanism of age-associated decline in antiviral CD8 T cell immunity (5R21AG083398-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10910173. Licensed CC0.

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