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Ketone Body Metabolism in CD8+ T Cell Responses

Award Number: R01AI165722
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/08/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Ketone Body Metabolism in CD8+ T Cell Responses - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $1,301,502 )
2025	2025	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Allergy and Infectious Diseases Research	001	4	6/4/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,301,502
2025	2024	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Allergy and Infectious Diseases Research	000	3	6/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,301,502

Issue Date FY: 2024 ( Subtotal = $650,751 )
2024	2024	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Allergy and Infectious Diseases Research	000	3	5/1/2024	NON-COMPETING CONTINUATION	$650,751
														Subtotal = $650,751

Issue Date FY: 2023 ( Subtotal = $650,751 )
2023	2023	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Allergy and Infectious Diseases Research	001	2	5/26/2023	NON-COMPETING CONTINUATION	$650,751
2023	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Allergy and Infectious Diseases Research	000	1	2/8/2023	NEW	$0
														Subtotal = $650,751

Issue Date FY: 2022 ( Subtotal = $650,751 )
2022	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Allergy and Infectious Diseases Research	000	1	6/8/2022	NEW	$650,751
														Subtotal = $650,751

Grand Total All Awards = $3,253,755

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Ketone Body Metabolism in CD8+ T Cell Responses

Award Number: R01AI165722

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/08/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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