# Resistance to T cell exhaustion

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $536,999

## Abstract

PROJECT SUMMARY
The overarching goals of this proposal are to define how intrinsic IL-2 production and extrinsic IL-2 signals act
in conjunction with helper CD4 T cell subsets to configure the exhausted CD8 T cell pool during chronic viral
infections and ascertain how these factors contribute to the restoration of responses following checkpoint
blockade therapies. This is significant for providing both fundamental insights into the regulation of exhausted
T cell ontogeny as well as for devising strategies to structure this ensemble to improve infection control while
avoiding immunopathology. The premise is founded in part on a series of exciting published and preliminary
findings showing that the pace of viral control can be predicted by the number of IL-2 producing CD8 T cells
present at the peak of the effector phase of the anti-viral response. Moreover, the initial formation of IL-2
producing CD8 T cells is accelerated during the earliest stages of chronic viral infections, but this population fails
to amplify, suggesting that they may instead serve as progenitors for the development of transitional and
terminally exhausted subsets. We also discovered that IL-2-producing effector CD8 T cells generated during
acute infections have superior protective powers and are resistant to full terminal exhaustion following adoptive
transfer and chronic viral challenge. Additionally, our preliminary findings demonstrate that the cell-autonomous
synthesis of IL-2 attenuates the ability to receive STAT5 signals. Collectively, these findings are consistent with
a model in which the initial manufacture of IL-2 enables exhausted precursor formation by restricting STAT5-
mediated signals, which are known to drive terminal differentiation. Further, we anticipate that the subsequent
extinguishment of IL-2 synthesis restores permissiveness to STAT5 signaling, which prompts the further
developmental transition of these precursors into more exhausted sub-populations. Our studies are designed to
pin-point how intrinsic cytokine production and extrinsic cytokine signals direct the formation and maintenance
of exhausted subsets, and provide new insights into the mechanisms that shape the efficacy of the anti-viral T
cell pool during chronic infections. We propose the following specific aims:
1. Define the contributions of IL-2-producing CD8 T cells to the formation of exhausted subsets.
2. Define the influence of functionally distinct CD4 helper subsets on the exhausted pool.
3. Determine the temporally distinct roles of IL-2 in structuring the exhausted pool.
Our studies take advantage of innovative and technically robust approaches to deconvolute the roles of distinct
cytokine producing subsets of anti-viral T cells during chronic infections. They are designed to impact the field
by advancing our understanding of how intrinsic cytokine production and extrinsic cytokine and cellular signals
integrate to configure the exhausted CD8 T cell pool and contribute to the cont...

## Key facts

- **NIH application ID:** 10909040
- **Project number:** 5R01AI156290-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Allan J Zajac
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $536,999
- **Award type:** 5
- **Project period:** 2021-09-22 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909040

## Citation

> US National Institutes of Health, RePORTER application 10909040, Resistance to T cell exhaustion (5R01AI156290-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10909040. Licensed CC0.

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