# T cell maintenance: molecular mediators of T cell differentiation and survival

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $499,619

## Abstract

Summary:
Despite extraordinary medical advances in the last century, infectious diseases remain the second leading
cause of death worldwide, and disease-associated morbidity causes immeasurable harm. The development of
new vaccines is, therefore, an imperative for improving global health. The ability of adaptive immune cells to
respond more rigorously after a primary exposure, preventing pathology, and in essence “remembering” the
infection is the basis for vaccination. A heterogeneous population of long-lived memory T cells mediate
protection from reinfection with previously encountered pathogens; keep chronic, opportunistic and latent
pathogens at bay; and defend against tumor growth and metastases. Thus, understanding how memory
lymphocytes are induced and sustained is of central importance in the rational design of new vaccines. Tissue-
resident memory T cells provide sentinel protection at body surfaces such as the intestinal epithelium, and
provide a first line of adaptive immune defense to reinfection. While we now know that tissue-resident T
memory cells provide an essential component of immune memory, the transcriptional pathways regulating their
formation, survival, and function, and how these relate to those that promote the formation of other memory
populations are poorly understood.
Improving our understanding of these topics will allow us to harness the immediate protective capacity of this
vital memory T cell population in tissues where infections typically begin and modulate activity in the context of
immunopathology. To this end, we present a preliminary in vivo functional screen that identifies numerous new
regulators of CD8+ tissue-resident memory T cell differentiation. Based on these novel findings, we propose to:
(1) Study how Runx3 and Blimp1 support the formation, homeostasis, and function of the CD8+ tissue-resident
memory T cell population. (2) Delineate the role of the bromodomain and extraterminal domain (BET)
epigenetic “reader” of histone acetylation, Brd4, in regulating gene expression during memory T cell
differentiation. (3) Define the transcriptional network that regulates CD8+ tissue-resident memory T cell
formation. By using single-cell sequencing and comparison of open chromatin regions in CD8+ tissue-resident
memory T cell populations to predict important transcriptional regulators, we will expand our in vivo screening
strategy to identify regulators of CD8+ tissue-resident memory cells. We will leverage the results to enhance
tissue-resident memory activity in the context of tumor growth and viral infection. By discovering the
transcriptional program and molecular regulators promoting differentiation, survival, and function of tissue-
resident memory T cells, we will identify novel targets that can be exploited in the strategic design of
therapeutic and protective vaccines, the development of which are of crucial importance to human health.

## Key facts

- **NIH application ID:** 10176359
- **Project number:** 5R01AI067545-15
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Ananda W Goldrath
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $499,619
- **Award type:** 5
- **Project period:** 2006-06-01 → 2022-09-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176359

## Citation

> US National Institutes of Health, RePORTER application 10176359, T cell maintenance: molecular mediators of T cell differentiation and survival (5R01AI067545-15). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10176359. Licensed CC0.

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