The regulation of CD8+ T cells by nutrient availability
type: CreativeWork
description: The aim of this project was to explore how nutrient availability control CD8+ T lymphocytes. The focus was the regulation and function of autophagy as CD8 T cells encounter amino acid deprived conditions. The study also examined the role of the AMP dependent kinase in CD8+ T cell responses to metabolic stress. To study autophagy a novel fluorescent autophagy reporter mouse model was used that allowed for quantitative analysis of autophagic flux at the single cell level in T lymphocytes. Using this fluorescent reporter naïve T cells were shown to have high levels of basal autophagy, and this was required to maintain cell survival and expression of the surface molecule L-selectin. Immune activation of CD8+ T cells resulted in downregulation of autophagy. The downregulation of autophagy was dependent on the availability of extracellular glucose and amino acids. We established that T cells switch off autophagy when they respond to immune activation and increase amino acid transport: they revert to autophagy when their capacity for amino acid transport is low. Effector CD8+ cytotoxic T cells generated in vitro displayed low levels of basal autophagy. This was increased upon removal of key cytokines or amino acids. It is generally considered that the amino acid sensing pathway that controls autophagy is mediated by the serine/threonine mTORC1. The current data found a modest role for mTORC1 as a regulator of autophagy in naive T cells and no role for mTORc1 in CTL. These data highlight that the regulatory processes that determine autophagy are not universal.To examine the role of autophagy in CD8+ cytotoxic T cells we used an inhibitor of VPS34, a phosphoinositide 3-kinase (PI3K) class III isoform that controls T cell autophagy. A key strategy was to use mass spectrometry to explore how Vps34 signalling pathways control the proteome restructuring that occurs in amino acid deprived CD8+ cytotoxic T cells to gain insights about how autophagy controls T cell function. Quanti…
abstract: The aim of this project was to explore how nutrient availability control CD8+ T lymphocytes. The focus was the regulation and function of autophagy as CD8 T cells encounter amino acid deprived conditions. The study also examined the role of the AMP dependent kinase in CD8+ T cell responses to metabolic stress. To study autophagy a novel fluorescent autophagy reporter mouse model was used that allowed for quantitative analysis of autophagic flux at the single cell level in T lymphocytes. Using this fluorescent reporter naïve T cells were shown to have high levels of basal autophagy, and this was required to maintain cell survival and expression of the surface molecule L-selectin. Immune activation of CD8+ T cells resulted in downregulation of autophagy. The downregulation of autophagy was dependent on the availability of extracellular glucose and amino acids. We established that T cells switch off autophagy when they respond to immune activation and increase amino acid transport: they revert to autophagy when their capacity for amino acid transport is low. Effector CD8+ cytotoxic T cells generated in vitro displayed low levels of basal autophagy. This was increased upon removal of key cytokines or amino acids. It is generally considered that the amino acid sensing pathway that controls autophagy is mediated by the serine/threonine mTORC1. The current data found a modest role for mTORC1 as a regulator of autophagy in naive T cells and no role for mTORc1 in CTL. These data highlight that the regulatory processes that determine autophagy are not universal.To examine the role of autophagy in CD8+ cytotoxic T cells we used an inhibitor of VPS34, a phosphoinositide 3-kinase (PI3K) class III isoform that controls T cell autophagy. A key strategy was to use mass spectrometry to explore how Vps34 signalling pathways control the proteome restructuring that occurs in amino acid deprived CD8+ cytotoxic T cells to gain insights about how autophagy controls T cell function. Quanti…
author: Youdale, Tom
language: eng
keywords: Immunology, Autophagy, Metabolism, T cells
date published: 2021
date modified: 2026-07-24T02:08:59Z
provider: University of Dundee
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Dundee