# Molecular Determinants of Tissue-resident Memory T cell Fate in Acute and Chronic Infection

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $1,948,930

## Abstract

OVERALL SUMMARY:
Mortality from infectious diseases remains the second leading cause of death worldwide; a further toll on
human health is exacted by disease-associated morbidity. The development of new vaccines is, therefore, an
important priority for improving global health. Immunological memory is a cardinal feature of adaptive immunity
and its induction is the underlying goal of vaccination. Long-lived memory T cells mediate protection from
reinfection with previously encountered pathogens; keep chronic, opportunistic and latent pathogens at bay;
and can serve as endogenous defenders against tumor growth and metastases. The memory T cell population
is heterogeneous, typically categorized into central memory cells found in the blood and lymphoid tissues, or
effector memory cells predominantly located in the blood and non-lymphoid tissues. The recent recognition of a
third subset of memory lymphocytes, termed tissue-resident memory cells (Trm), that reside strictly within
tissues and do not recirculate requires a revision of our understanding of memory T cell differentiation. Tissue-
resident T cells provide essential sentinel protection at body surfaces such as the intestinal epithelium, and,
are now clearly understood to be among the key `first responders' in many infection settings. Although we now
know that resident-memory cells are an essential component of immune memory, little is known about the
transcriptional pathways regulating their formation, survival and function.
Improving our understanding of these topics will allow us to harness the immediate protective capacity of this
vital memory T cell population and modulate activity in the context of immunopathology. To this end, we
propose three synergistic projects that all leverage novel single-cell, genomic and computational analyses
provided by two Cores to: 1) Define the unanticipated roles of key transcription factors in Trm formation and
identify novel molecular determinants of Trm differentiation and homeostasis; 2) Identify early molecular
regulators of Trm cell fate specification within different tissues in the context of acute and chronic infections
using single-cell analyses of gene expression and computational approaches; 3) Define exhausted Trm during
chronic viral infection and identify core regulators that determine their accumulation and hypo-functional state.
Understanding the generation and homeostasis of tissue-resident memory cells will allow the exploitation of the
immediate protective capacity of this vital memory population and provide strategies to modulate this activity in
the context of immunopathology. We have assembled a team of five laboratories, which together possess the
tools and expertise to resolve the transcriptional network driving memory T cell formation and exploit this
knowledge to realize advances in regulating immunity in tissues. !

## Key facts

- **NIH application ID:** 10214451
- **Project number:** 5P01AI132122-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Ananda W Goldrath
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,948,930
- **Award type:** 5
- **Project period:** 2018-07-17 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214451

## Citation

> US National Institutes of Health, RePORTER application 10214451, Molecular Determinants of Tissue-resident Memory T cell Fate in Acute and Chronic Infection (5P01AI132122-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10214451. Licensed CC0.

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