# The developmental layers in the CD8+ T cell response to chronic infection

> **NIH NIH R01** · CORNELL UNIVERSITY · 2020 · $477,987

## Abstract

Project Summary/Abstract
Following infection, a small percentage of effector CD8+ T cells survive and transition into the long-lived memory
pool. Given that memory CD8+ T cells are key to immunity against intracellular pathogens, it is essential that we
understand the mechanisms by which they are formed. This question has been at the forefront of the field for
decades. The current dogma suggests that a single lineage of naïve T cells can give rise to different short- and
long-lived subsets of effector or memory T cells, depending upon the cues (inflammation, antigen) they encounter
during infection. However, in the last funding cycle, we discovered that the propensity for T cells to adopt
particular fates during infection is, instead, pre-programmed prior to infection, and is largely determined by their
developmental origin. As all of our work to date has been performed in the context of acute infections, the major
goal of our renewal proposal is to extend our studies to chronic infection, where we will determine how
heterogeneity within the memory pool is linked to variation in the developmental origins of the responding cells.
To accomplish this goal, we will combine our novel fate mapping system with the well-characterized mouse
model of LCMV infection to dissect the functional heterogeneity within the memory pool. Our preliminary studies
indicate that adult-derived cells preferentially become functionally exhausted during chronic infection compared
to fetal-derived cells. However, clonal exhaustion of adult-derived CD8+ T cells can be prevented by
overexpression of Lin28b, a master regulator of fetal-derived immune cells. Based on these findings and our
published work, we hypothesize that the fate of CD8+ T cells during chronic infection is linked to their
developmental origin. In the first aim, we will determine how developmental origin alters the CD8+ T cell response
to chronic pathogens. In the second aim, we will examine how developmental origin alters gene regulatory
programs in CD8+ T cells during chronic infection. In the last aim, we will determine how developmental
differences in Lin28b influence the ability of CD8+ T cells to respond to chronic infection. Knowledge gained from
these studies is expected to provide a better understanding of the mechanisms regulating the CD8+ T cell
response to chronic pathogens, which is essential for developing more precise and effective strategies to restore
functionality in exhausted CD8+ T cells.

## Key facts

- **NIH application ID:** 10001423
- **Project number:** 5R01AI110613-07
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** ANDREW W GRIMSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $477,987
- **Award type:** 5
- **Project period:** 2014-03-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001423

## Citation

> US National Institutes of Health, RePORTER application 10001423, The developmental layers in the CD8+ T cell response to chronic infection (5R01AI110613-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001423. Licensed CC0.

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