# Ketone Body Metabolism in CD8+ T Cell Responses

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2024 · $650,751

## Abstract

ABSTRACT
It has been believed that infection-fighting T cells primarily use glucose to fuel host defense against viruses
and bacteria; however, using new in vivo metabolite profiling techniques, it has recently been found that
glucose is not the primary fuel for mitochondrial energy (ATP) production in CD8+ T cells responding to
infection in vivo, particularly in later phases of infection. This presents the immunometabolism community with
a critical need to define and understand the metabolites that sustain infection-fighting CD8+ T cells. This
knowledge is crucial for developing effective immuno-metabolic interventions that strengthen host defense
and/or enhance immunization strategies. Preliminary data point to ketone bodies—a metabolite class enriched
in the blood in response to infection, fasting, and certain diets—as a key fuel for CD8+ T cell effector function,
with data suggesting that ketone body availability influences T cell-mediated adaptive immunity by regulating
effector function (i.e., cytokine production) at the epigenetic level. However, the full impact of T cell-intrinsic
ketone body metabolism on CD8+ T cell responses remains uncharacterized.
OVERALL OBJECTIVE: to characterize the mechanisms by which T cell-intrinsic ketone body metabolism
(“ketolysis”) impacts CD8+ T cell metabolism and function during immune responses to infection, and to
determine the role of systemic ketone body metabolism in CD8+ T cell function and host defense.
HYPOTHESIS: T cell-intrinsic ketone body metabolism is a non-redundant pathway supporting host defense
by fueling and directing CD8+ T cell bioenergetics and effector function in vivo. SPECIFIC AIMS: (1)
Characterize ketone body metabolism in CD8+ T cells and its impact on CD8+ T cell-mediated immune
responses, (2) Deconstruct the mechanisms by which ketone body metabolism impacts T cell effector function,
(3) Dissect the impact of systemic ketone body metabolism on CD8+ T cell responses.
IMPACT: Upon completion, this proposed research will have determined how activated CD8+ T cells utilize
ketone bodies, dissected the impact of ketone bodies on CD8+ T cell effector function (primary infection
clearance) and memory responses (long-term immunity), and defined how systemic ketone body availability is
controlled and impacts CD8+ T cell-mediated host defense. By defining the role of ketone body metabolism in
protective CD8+ T cell-mediated immune responses, we will have laid the groundwork for defining dietary and
pharmacological interventions to optimize endogenous host defenses to boost clearance of infections as well
as enhance immunization strategies.

## Key facts

- **NIH application ID:** 10849931
- **Project number:** 5R01AI165722-03
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Russell Graham Jones
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $650,751
- **Award type:** 5
- **Project period:** 2022-06-08 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849931

## Citation

> US National Institutes of Health, RePORTER application 10849931, Ketone Body Metabolism in CD8+ T Cell Responses (5R01AI165722-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10849931. Licensed CC0.

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