# Project 1: Immune Memory

> **NIH NIH U19** · EMORY UNIVERSITY · 2020 · $1,153,869

## Abstract

The cardinal properties of memory CD8 T cells are their longevity, rapid elaboration of effector functions and the
ability to proliferate upon re-exposure to the pathogen. We have been addressing fundamental questions about
the origin and differentiation of human memory CD8 T cells using the live attenuated yellow fever virus vaccine
(YFV-17D) and have made substantial progress during the current cycle of funding. Using in vivo deuterium
labeling to mark virus specific CD8 T cells, we have shown that the memory pool originates from CD8 T cells
that divided extensively during the first two weeks after infection and is then maintained by quiescent cells that
divide less than once a year. Although these long-lived YFV specific memory CD8 T cells did not express effector
molecules and had a transcriptional profile similar to naïve CD8 T cells, their epigenetic landscape resembled
that of virus specific effector CD8 T cells. This open chromatin profile at effector genes was maintained in
memory CD8 T cells isolated even a decade after vaccination, indicating that these cells retain an epigenetic
fingerprint of their effector history and remain poised to respond rapidly upon re-exposure to the pathogen. These
findings have prompted us to ask several new questions about human memory CD8 T cell differentiation.
Specifically, what are the transcriptional and epigenetic changes taking place at the single cell level during this
effector to memory cell transition? Can we identify fate-permissive and fate-locked YFV specific effector CD8 T
cells and follow their differentiation trajectories longitudinally? Is the memory differentiation paradigm that we
have defined with our YFV-17D studies generalizable to other acute viral infections? Will memory CD8 T cells
after different acute viral infections look the same or will they be different? Does childhood vaccination result in
the same memory differentiation program as vaccination of adults? Finally, how are tissue resident memory cells
distributed, and how do the phenotype, transcriptional, and epigenetic signatures of these cells compare to the
long-lived memory CD8 T cells we have found in the blood. To address these questions the following Specific
Aims are proposed: Aim 1. Mapping the differentiation trajectories of virus specific effector CD8 T cells
as they transition to long-lived memory. Aim 2. To characterize memory CD8 T cells responses to
childhood vaccines and acute viral infections. Aim 3. To analyze virus-specific tissue-

## Key facts

- **NIH application ID:** 9893787
- **Project number:** 5U19AI057266-17
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Rafi Ahmed
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,153,869
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893787

## Citation

> US National Institutes of Health, RePORTER application 9893787, Project 1: Immune Memory (5U19AI057266-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9893787. Licensed CC0.

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