# Formation, Positioning, Motility, and Function of Tissue Resident Memory CD8+ T cells After Influenza Infection

> **NIH NIH P01** · UNIVERSITY OF ROCHESTER · 2020 · $407,900

## Abstract

PROJECT SUMMARY/ABSTRACT – PROJECT 3
Tissue resident memory T cells (TRM) are non-recirculating CD8+ T cells that become established in
peripheral tissues after an infection. Upon re-encounter with the same or related pathogen(s), these memory T
cells rapidly reactivate and provide immediate effector function that can mean the difference between life and
death in a lethal challenge model. They tend to be specific for conserved antigens, and in the case of
influenza, could be part of the solution to achieving more broadly cross-reactive and universal vaccine.
Understanding how they are regulated, how they mediate optimal protection, and how they are established and
maintained are critical goals of this project. Besides the markers used to identify the T cell types (CD3, CD8,
CD44, CD62L, CD69), several other cell surface markers are used to identify memory T cell subsets in the
tissues. CD49a, when paired to integrin beta-1 to form VLA-1, is a receptor for collagen in the extracellular
matrix and is the prototypic TRM marker first used to define these cells in the tissue by us in 2004. CD103,
when paired with beta-7 integrin, binds to E-cadherin expressed in the junctions between epithelial cells. These
“markers' of TRM are critical to their establishment and function, yet little has been done to determine the in
vivo functions of CD49a and CD103. We propose to test hypotheses related to how each of these adhesion
molecules acts to position memory T cells in different anatomical locations, regulate communication with the
epithelium, are associated with genetic programming linked to functional differentiation, thereby regulating
CD8+ T cell motility, survival, and optimal immune protection. The Specific Aims are:
Aim 1: Determine the mechanisms that determine differentiation, establishment, and maintenance of
TRM subsets after influenza infection.
Aim 2: Investigate mechanisms of T cell-epithelial cell-matrix interactions required for motility and
positioning in the airways.
Aim 3: Determine the functions of CD49a and CD103 in optimizing immune protection.
To achieve these aims, we use combinations of genomics, flow cytometry, in vitro and in vivo models to study
the differentiation and function of these cells. A core technology employed is intravital multiphoton microscopy
(IV-MPM) applied to a live animal model of influenza tracheitis that our lab developed. We extend this
approach to an innovative in vitro system using primary airway organoid cultures incorporating influenza
infection and virus-specific CD8 T cells to study fine aspects of the mechanisms regulating cell motility and T-
cell/epithelial cell interactions. The results of our studies will lead to novel ways to optimize immune protection
from influenza and reduce the burden of disease.

## Key facts

- **NIH application ID:** 10002196
- **Project number:** 5P01AI102851-07
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** DAVID James TOPHAM
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $407,900
- **Award type:** 5
- **Project period:** 2014-06-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002196

## Citation

> US National Institutes of Health, RePORTER application 10002196, Formation, Positioning, Motility, and Function of Tissue Resident Memory CD8+ T cells After Influenza Infection (5P01AI102851-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10002196. Licensed CC0.

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