# Impaired NK cell function by the synthetic food additive tBHQ

> **NIH NIH R21** · MICHIGAN STATE UNIVERSITY · 2022 · $187,992

## Abstract

PROJECT SUMMARY
Respiratory viruses, such as influenza, kill tens of thousands of people annually in the U.S. and worldwide,
making it the eighth leading cause of death nationally. One of the perplexing aspects of this disease is the
variability in interindividual response. Whereas many individuals experience manageable symptoms, others
contract serious disease requiring hospitalization. While it is well established that NK cells are critical for early
control of influenza infection, exciting new studies indicate that NK cells also provide an important memory
response to influenza, a feature previously thought to be reserved for T cells and B cells. Our data indicate that
a low dose of the synthetic food additive, tert-butylhydroquinone (tBHQ), impairs NK cell effector function and
adversely impacts the innate immune response to influenza. Specifically, our recently published study shows
that treatment of activated NK cells with tBHQ in vitro results in decreased induction of interferon-gamma
(IFNγ), perforin and granzyme—all of which are critical molecules for controlling spread of viral infection within
the host. Furthermore, our studies show that mice on a low-dose tBHQ diet have an impaired NK cell response
to influenza as evidenced by a decreased percentage of IFNγ+ NK cells in the lung, decreased IFNγ gene
expression and diminished induction of IFNγ and granzyme B. These effects precede an impaired T cell
response to influenza, increased viral burden and worsened bronchostitial pneumonia, which is consistent with
recent studies showing that the NK cell response is critical for optimal T cell activity in influenza. We have
previously established that tBHQ is a potent and robust activator of Nrf2 in immune cells, which points to a
possible mechanism for these effects. These preliminary data serve as the foundation for our central
hypothesis, which is tBHQ diminishes NK cell effector function and memory through a Nrf2-dependent
mechanism. We propose to test this hypothesis in two specific aims. Aim 1 is to determine the mechanism by
which tBHQ inhibits NK cell activation and effector function. These studies will be conducted in wild-type and
Nrf2-deficient models to determine the role of Nrf2 in these effects. We will also perform single-cell RNA-
sequencing to determine the effect of tBHQ on functionally-distinct NK cell subsets. Aim 2 is to characterize the
effect of tBHQ on the development of NK cell memory. This aim will utilize flow cytometry to identify memory
NK cells and conditional knockout mice to determine the role of Nrf2 on the functionality of these cells.

## Key facts

- **NIH application ID:** 10525961
- **Project number:** 1R21ES033830-01A1
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Elizabeth M. Gardner
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $187,992
- **Award type:** 1
- **Project period:** 2022-09-06 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525961

## Citation

> US National Institutes of Health, RePORTER application 10525961, Impaired NK cell function by the synthetic food additive tBHQ (1R21ES033830-01A1). Retrieved via AI Analytics 2026-08-11 from https://api.ai-analytics.org/grant/nih/10525961. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*