# Elucidating the Mode of Action of "Tfh-like" Resident Memory CD4+T cells in Human Lung

> **NIH NIH R21** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $254,250

## Abstract

Project Summary
Influenza infections cause substantial morbidity and mortality worldwide. While vaccination is considered to
provide protection, the antibody response induced by current seasonal vaccines is generally short-lived. In
contrast, natural influenza infection induces durable protective immunity against future influenza virus
infections. The immune mechanisms and pathways that are linked with durable protection by natural infection
remain unclear particularly in humans. Studies in animal models show that influenza infection, but not
immunization with inactivated virus, generates influenza-specific lung tissue-resident memory T (TRM) cells.
TRM are retained for a long time locally, and there is evidence that influenza-specific TRM are far more
efficient than their splenic counterpart for protection from influenza infection. Infection with influenza virus also
induces lung-resident memory B (BRM) cells that rapidly produce specific Abs in the lung following infection
challenge. Whereas these observations suggest a key role of influenza-specific lung BRM at the frontline upon
re-infection, the mechanism by which lung BRM differentiate into Ab-producing cells remains unknown. We
hypothesize that a subset(s) of influenza-specific lung CD4 TRM display properties similar to T follicular helper
(Tfh) cells, and that this subset(s) interact with influenza-specific memory B cells in human lung for rapid local
Ab response. In this proposal, we will leverage our extensive expertise in human CD4+ T cell subsets to define
a “Tfh-like” subset within human lung CD4 TRM, and determine their mode of action on lung BRM. Aim 1 will
define the phenotype of “Tfh-like” CD4 TRM in human lung. By using Cellular Indexing of Transcriptomes and
Epitopes by Sequencing (CITE-seq), we will comprehensively analyze the transcriptional heterogeneity among
human lung CD4+ T cells differentially expressing surface markers, and aim to identify the cell population
enriched with the Tfh-gene signature. We will also assess the phenotype of influenza-specific CD4 TRM in
human lung by using the IRF4 assay that we have recently established. Aim 2 will comprehensively define the
subsets of influenza HA-specific B cells in human lung. By co-culturing “Tfh-like” CD4 TRM with lung BRM, we
will analyze whether the T cells induce B cell differentiation into influenza Ab-producing cells. We will further
determine the helper mechanism by blocking several candidate molecules. As such, our study aims to identify
the major T and B cell subsets in human lung responsible for rapid local Ab response. We anticipate that our
study will increase our knowledge in the local immune protection mechanism of human lung and provide
significant insight into the design of efficient influenza vaccines.

## Key facts

- **NIH application ID:** 10039182
- **Project number:** 1R21AI153673-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Hideki Ueno
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $254,250
- **Award type:** 1
- **Project period:** 2020-06-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10039182

## Citation

> US National Institutes of Health, RePORTER application 10039182, Elucidating the Mode of Action of "Tfh-like" Resident Memory CD4+T cells in Human Lung (1R21AI153673-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10039182. Licensed CC0.

---

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