Metabolic regulation of the anti-helminth CD4+ T cell response
department or school: Science, Faculty of
department or school: Microbiology and Immunology, Department of
data provider: DSpace
degree campus: UBCV
creator: Heieis, Graham Anthony
issued: 2020-01-28T21:42:33Z
issued: 2019
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Cellular metabolism is intricately linked to the activation and effector function of CD4+ T cells. Activation triggers an increase in glycolysis, which is thought to fuel the necessary biosynthetic demands of growth and proliferation. Recent work suggests that glycolytic activity further coordinates distinct functions in different T helper subsets. Thus far, however, little has been elucidated about the regulation of metabolism in Th2 cells. Using in vitro cultures and in vivo infection models, I compared glycolysis in Th1 and Th2 cells generated from cytokine-reporter mice. This revealed that Th2 cells from infected mice maintain a low glycolytic rate that more closely resembles that of naïve T cells. I hypothesized Th2 cells may be metabolically suppressed by helminths during infection, and therefore tested the capability of purified helminth products to alter glycolysis of in vitro polarized Th2 cells. Cytokine production was inhibited, but an effect on glycolysis could not be consistently demonstrated. However, signalling through the metabolic regulator, mTOR, was reduced in T cells from helminth infected mice compared to controls, supporting the possibility of metabolic modulation in vivo. I questioned whether Th2 cell glycolysis was regulated after exiting the lymph node. By assessing Th2 cell metabolism from the effector site, I discovered that fatty acid metabolism, and not glycolysis, was upregulated in the peripheral tissue. Fatty acid uptake was enhanced in cells expressing the IL-33 receptor, ST2. These cells highly co-expressed programmed death protein 1 (PD-1), a known regulator of T cell metabolism. Hence, I predicted that PD-1 signalling promotes ST2 expression in the tissue. Accordingly, ex vivo stimulation of sorted Th2 cells through PD-1 increased ST2 expression. From these data I propose that PD-1 signalling overcomes a metabolic checkpoint to permit alarmin-responsiveness and tissue-localized cytokine production. Overall, these findings illustra…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/73402
note: METABOLIC REGULATION OF THE ANTI-HELMINTH CD4+ T CELL RESPONSE by Graham Anthony Heieis B.Sc., The University of British Columbia, 2014 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate and Postdoctoral Studies (Microbiology & Immunology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2020 ÓGraham Anthony Heieis, 2020 ii Committee Page The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Metabolic regulation of the anti-helminth CD4+ T cell response submitted by Graham Heieis in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Microbiology and Immunology Examining Committee: Dr. Perona-Wright, Microbiology and Immunology Co-supervisor Dr. Pauline Johnson, Microbiology and Immunology Co-supervisor Dr. Megan Levings, Surgery Supervisory Committee Member Dr. Ninan Abraham, Microbiology and Immunology University Examiner Dr. Fumio Takei, Pathology and Laboratory Medicine University Examiner Additional Supervisory Committee Members: Dr. Kenneth Harder, Microbiology and Immunology Supervisory Committee Member Supervisory Committee Member iii Abstract Cellular metabolism is intricately linked to the activation and effector function of CD4+ T cells. Activation triggers an increase in glycolysis, which is thought to fuel the necessary biosynthetic demands of growth and proliferation. Recent work suggests that glycolytic activity further coordinates distinct functions in different T helper subsets. Thus far, however, little has been elucidated about the regulation of metabolism in Th2 cells. Using in vitro cultures and in vivo infection models, I compared glycolysis in Th1 and Th2 cells generated from cytokine-reporter mice. This revealed that Th2 cells from infected mice maintain a low glycolytic rate that more closely resembles that of naïve T cell…
has type: Thesis/Dissertation
date issued: 2020-05
is shown at: 10.14288/1.0388465
language: eng
degree discipline: Microbiology and Immunology
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/73402