# Metabolic heterogeneity of tissue resident memory T cells in the liver

> **NIH NIH R21** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2020 · $240,500

## Abstract

SUMMARY
 Memory CD8+ T cells are formed after pathogen clearance in acute infection to survey the body and
mount a faster, stronger response upon reexposure to the pathogen. These memory CD8+ T cells can take
residence in peripheral tissue as tissue resident memory T cells (TRM) that can act as a first-line of defense
against viral infection and tumor recurrence within their respective tissues. For TRM cells to take up residence in
different tissues, they must adapt their transcriptional, metabolic, and functional states to persist in widely varying
architectural and metabolic environments. Indeed, while TRM cells from different tissues exhibit common
transcriptional signatures, they also display heterogeneity in metabolic gene expression that likely reflects
adaptation to the different tissue environments. Understanding how T cells adapt to various metabolic
environments would broaden our knowledge of organ-specific immunity and provide stronger protections against
chronic infection and tumors.
 To study how TRM cells adapt to varying metabolic conditions, we seek to study how TRM cells take up
residence in the liver, which is organized into distinguishable metabolic zones. The liver produces bile acids
(BAs) to aide in digestion, but BAs can induce a variety of responses and stresses in cells. Analysis of RNA
sequencing data showed that liver TRM cells exhibit a high expression of bile acid receptors and transporters that
reflect the high bile acid content in the liver. In particular, they express the bile acid receptors CAR and TGR5,
and the bile acid transporter MDR1, which play roles in bile acid sensing and homeostasis. What is unknown in
the field is how TRM adaptation to the liver by expressing these receptors affects their formation, function and
survival. We hypothesize that liver CD8+ TRM cells display heterogeneity within the liver reflective of the
metabolic zones they inhabit, and express CAR, MDR1, and TGR5 in order to adapt the bile acid-rich
environment of the liver. To examine this idea, we will first profile the heterogeneity of TRM with a combination
of imaging mass spectrometry, flow cytometry, Seahorse assays, and RNA sequencing to correlate expression
of metabolic genes and immunological function in TRM cells with their location within the liver. Next, we will explore
the specific roles of CAR and MDR1 in TRM adaptation and function through flow cytometry, mass spectrometry,
Seahorse assays, and RNA sequencing. We will similarly study TGR5, which is highly expressed on liver TRM
cells, but has been reported to have anti-inflammatory functions. These results could lead to a better
understanding of how TRM cells adapt to organ-specific metabolic environments, and the development of novel
vaccination and therapeutic strategies to confer protection against liver infection and cancer.

## Key facts

- **NIH application ID:** 9959243
- **Project number:** 1R21AI151562-01
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Susan M Kaech
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $240,500
- **Award type:** 1
- **Project period:** 2020-03-06 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959243

## Citation

> US National Institutes of Health, RePORTER application 9959243, Metabolic heterogeneity of tissue resident memory T cells in the liver (1R21AI151562-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9959243. Licensed CC0.

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