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The role of Nrf2 in T cell function and influenza

Award Number: R01ES035763
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/06/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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The role of Nrf2 in T cell function and influenza - Despite considerable efforts toward vaccination, influenza and its complications continue to kill tens of thousands of people annually in the U.S., making it the eighth leading cause of death nationally. There is considerable interindividual variability in the immune response to influenza, which is due to the polymorphic nature of the immune system and other unidentified factors. Our preliminary data suggest that exposure to the synthetic food additive tert-butylhydroquinone (tBHQ) is one factor that can impact the effectiveness of the adaptive immune response to influenza. Our published studies demonstrate that tBHQ inhibits the differentiation of CD4 T cells into Th1 cells, a key cell type in antiviral host defense that is particularly important in the development of immunological memory to influenza. Our preliminary data indicate that tBHQ also markedly inhibits CD8 T cell function. Furthermore, we have found that mice on a tBHQ diet have a markedly impaired T cell response to influenza (A/PR/8/1934 H1N1 strain). While these studies indicate that tBHQ impairs both CD4 and CD8 T cell responses to viral pathogens, the underlying mechanism remains unknown. Elucidation of this mechanism will not only provide insight into ways to minimize the impact of diet on the response to viral pathogens, but could also reveal a novel regulatory pathway in T cells that is important for T cell polarization and function. The central hypothesis for this project is that tBHQ activates the transcription factor, Nrf2, which inhibits T-bet-dependent development of antiviral CD4 and CD8 effector T cells. This hypothesis is based in part upon our preliminary studies demonstrating that mice on a tBHQ diet have an impaired immune response to influenza. Specifically, mice exposed to tBHQ through diet, at concentrations present in human food, show a marked decrease in the production of cytokines, such as IFNγ, TNFα and IL-6, a reduction in the numbers of influenza-specific CD4 and CD8 T cells and increased viral burden. In addition to diminished primary response (i.e. first exposure to influenza), mice on a tBHQ diet also show an impaired memory response to influenza, causing much greater decrease in body weight and decreased numbers of influenza-specific CD4 and CD8 T cells. Furthermore, our in vitro studies demonstrate that robust activation of Nrf2 by tBHQ impairs CD4 and CD8 T cell function, as evidenced by decreased Th1 polarization, impaired IFNγ, IL-2 and granzyme B induction by activated CD8 T cells and diminished expression and activity of T-bet, a transcription factor that is critical for Th1 polarization and CD8 T cell effector function. We propose to test our hypothesis by 1) determining the mechanism by which activation of Nrf2 by tBHQ inhibits Th1 differentiation and the effector function of CD8 T cells, 2) determining the mechanism by which tBHQ inhibits the primary adaptive immune response to influenza and 3) identifying the role of Nrf2 in the impaired memory T cell response to influenza in tBHQ-fed mice.


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: 2026 ( Subtotal = $510,551 )
2026	2026	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD	EAST LANSING	MI	48824	INGHAM	USA	Environmental Health	000	3	4/17/2026	NON-COMPETING CONTINUATION	$510,551
														Subtotal = $510,551

Issue Date FY: 2025 ( Subtotal = $543,080 )
2025	2025	HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES	426 AUDITORIUM RD	EAST LANSING	MI	48824	INGHAM	USA	Environmental Health	000	2	3/27/2025	NON-COMPETING CONTINUATION	$543,080
														Subtotal = $543,080

Issue Date FY: 2024 ( Subtotal = $510,251 )
2024	2024	HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES	426 AUDITORIUM RD	EAST LANSING	MI	48824	INGHAM	USA	Environmental Health	000	1	7/5/2024	NEW	$510,251
														Subtotal = $510,251

Grand Total All Awards = $1,563,882

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The role of Nrf2 in T cell function and influenza

Award Number: R01ES035763

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/06/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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