Understanding Metabolic Adaptation Of T Cells During Activation And Nutrient Limitation

Loading...
Thumbnail Image
Degree type
Doctor of Philosophy (PhD)
Graduate group
Immunology
Discipline
Subject
effector
glycolysis
IFN-y
memory
metabolism
mitochondria
Allergy and Immunology
Immunology and Infectious Disease
Medical Immunology
Funder
Grant number
License
Copyright date
2019-04-02T20:18:00-07:00
Distributor
Related resources
Contributor
Abstract

Immune cells employ a diverse array of metabolic programs upon stimulation that have far-reaching consequences outside of energy production. Activated T cells require glycolysis to generate the biosynthetic intermediates for proliferation and to enhance effector functions. Due to the disorganized vasculature of solid tumors and the highly glycolytic nature of tumor cells, T cells must compete for glucose with tumor cells in a nutrient-depleted environment. We hypothesized that cells that traffic to inflamed, nutrient-limiting environments in the periphery (effector memory T cells, TEM) may have enhanced abilities to adapt to nutrient limitation compared to cells that largely reside in nutrient-rich lymphoid organs (naïve and central memory T cells, TN and TCM respectively). We demonstrate that TN and TCM rely on fatty acid metabolism to survive and proliferate when glucose is limiting, whereas TEM do not. Furthermore, we find the reliance on fatty acid metabolism in limiting glucose by TN and TCM cells regulates IFN-γ production. Thus the first section of my thesis identifies a novel regulatory interaction between fatty acid synthesis and effector function. Other byproducts of metabolic pathways can also affect immune cell function. Recent work has suggested that reactive oxygen species are released following activation, which promote proliferative signals in T cells such as IL-2 production. The second section of my thesis investigates how T cells increase reactive oxygen species (ROS) production following activation. Using transmission electron microscopy we observe dramatic alterations to mitochondrial morphology following T cell activation. Mitochondria significantly increase in size and their cristae lose parallel patterning during the first 48 hours of T cell activation. Mitochondrial swelling and cristae disturbance are glucose and mTORC1 dependent, and highly reversible. Interestingly, we find that mitochondrial swelling does not correlate to oxidative phosphorylation rate, but strongly correlates to ROS production. We speculate that these mitochondrial changes are required to create the ROS necessary for subsequent IL-2 production and T cell proliferation. Together these data demonstrate novel relationships between cellular metabolism and cytokine production in CD4 T cells. By identifying how metabolites specifically affect immune function, we hope to exploit these discoveries in future cancer immunotherapies.

Advisor
James L. Riley
Date of degree
2018-01-01
Date Range for Data Collection (Start Date)
Date Range for Data Collection (End Date)
Digital Object Identifier
Series name and number
Volume number
Issue number
Publisher
Publisher DOI
Journal Issue
Comments
Recommended citation