# Molecular regulation of protective CD8 immunity against influenza infection

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $488,039

## Abstract

Summary/Abstract
Tissue-resident memory T cells (TRM) that reside within the non-lymphoid tissues provide superior immunity
against a variety of pathogens including influenza virus infection compared to the circulating memory T
cells.
Currently,
the molecular and metabolic mechanisms regulating CD8 TRM programming, maintenance
and functions in the tissue are incompletely understood. Unravelling novel mechanisms by which lung
protective TRM responses are regulated following influenza infection may aid the design of future influenza
therapeutics and/or influenza vaccines. The long-term objective of this grant is to investigate the molecular
mechanisms regulating the development of protective CD8 T cell immunity in the respiratory tract during
influenza infection.
We recently have identified the transcription factor, Bhlhe40, plays a central role in regulating the fitness
and function of influenza-specific CD8 TRM. In this application, we hypothesize that non-canonical TGFbR
signaling, through TAK1/Gadd45b-dependent pathway, facilitates Bhlhe40 expression and TRM
mitochondrial health, thereby promoting the maintenance and protective functions of TRM against influenza
infection. Three specific Aims are proposed: Aim 1: To determine the underlying mechanisms by which
Bhlhe40 promotes protective TRM responses following influenza infection. Aim 2: To elucidate the roles of
non-canonical TGFBR signaling, mediated through TAK1-Gadd45b pathway, in regulating TRM development
and/or maintenance. Aim 3: To define the roles of mitochondrial fitness, modulated by TAK1-Gadd45b-
Bhlhe40 pathway, in regulating TRM responses and protective function.
Each year, influenza virus infects 5–10% of adults and 20–30% of children, killing as many as 500,000
people globally. Understanding the cellular and molecular mechanisms regulating the formation and/or
maintenance of lung protective TRM responses following influenza infection and/or immunization may aid the
design of future influenza therapeutics and novel influenza vaccines.

## Key facts

- **NIH application ID:** 10067787
- **Project number:** 2R01AI112844-07A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Jie Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $488,039
- **Award type:** 2
- **Project period:** 2015-02-10 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067787

## Citation

> US National Institutes of Health, RePORTER application 10067787, Molecular regulation of protective CD8 immunity against influenza infection (2R01AI112844-07A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10067787. Licensed CC0.

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