# Defining the impact of pre-existing memory T cells in human immunity

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $457,946

## Abstract

Project Summary
Globally, more than 18 million people are infected with HIV, 10.4 million people are infected with tuberculosis,
and over 200 million people become infected by malaria in a single year. There is a critical unmet need for
vaccines against these infections and studies using mouse models have not yielded effective vaccines. The
development of a functional memory response that enables the immune system to react quickly and robustly to
previously experienced pathogens is the single most important factor for vaccine efficacy. Defining the
mechanisms by which memory T cell responses are generated in humans is essential for developing
efficacious vaccines. Previous studies in laboratory mice have shown that primary T cell responses to novel
antigens originate from naïve T cells. However, mice maintained under specific pathogen-free conditions are
vastly different from humans in the extent of their microbial exposure. Our lab was the first to describe that
human adults possess pre-existing memory phenotype (TMP) CD4+ T cells specific for viral antigens to
which they have never been exposed. We further demonstrated that nearly a quarter of HIV-reactive T cell
clones isolated from uninfected people also respond to unrelated microbial peptides, suggesting that these TMP
cells are broadly cross-reactive to many different antigens. The development of TMPs likely reflects the
cumulative exposure to environmental antigens following thymic development and these cells may be the
earliest cells to respond during a primary infection. Here, we will build on these foundations and use yellow
fever virus (YFV) vaccination as a model to test the hypothesis that pre-primed TMP cells generate potent
effectors and preferentially give rise to post-vaccination memory T cells in humans. We will use a
specific cell-labeling reagent called tetramers to tag T cells that recognize YFV antigens before vaccination and
at multiple times after vaccination. This will allow us to trace YFV-reactive T cells directly ex vivo as they
evolve following vaccination. Specifically, we will address the following questions: (1) does TMP cells have a
greater functional diversity and plasticity compared to classic memory T cells; (2) does the abundance or the
composition of TMP cells predict the rate and the magnitude of the effector response; (3) does TMP cells
preferentially give rise to post-vaccination memory T cells? This study will reveal basic paradigms of how pre-
existing memory precursors impact the potency and durability of CD4+ T cell immunity in vaccination.
Understanding how the environment conditions the human T cell repertoire to influence later responses
extends beyond vaccine efficacy and is broadly relevant to many areas of human health, including infection,
autoimmunity, and cancer surveillance

## Key facts

- **NIH application ID:** 9989042
- **Project number:** 5R01AI134879-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Laura Su
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $457,946
- **Award type:** 5
- **Project period:** 2017-09-25 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989042

## Citation

> US National Institutes of Health, RePORTER application 9989042, Defining the impact of pre-existing memory T cells in human immunity (5R01AI134879-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9989042. Licensed CC0.

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