Molecular mechanisms of antigen-specific memory CD4 T cell tolerance and the implications for tolerogenic therapy

Gray, Joshua (2019) Molecular mechanisms of antigen-specific memory CD4 T cell tolerance and the implications for tolerogenic therapy. PhD thesis, University of Glasgow.

Due to Embargo and/or Third Party Copyright restrictions, this thesis is not available in this service.

Abstract

A major goal in autoimmune therapies is to tolerise immune cells, such as memory CD4 T cells, that co-ordinate tissue damage. Memory CD4 T cells exhibit greater responses upon subsequent re-exposure to their cognate antigen. Whilst the mechanisms of primary effector or naïve CD4 T cells are quite well defined, much less is known about the induction of tolerance within memory CD4 T cells. Improving knowledge of the poorly defined mechanisms of tolerance induction could refine and advance current therapies. Previous work in the lab has demonstrated that memory CD4 T cells located in lymphoid organs are susceptible to tolerogenic stimulation upon subsequent restimulation in vivo. This resulted in the Ag-specific deletion of these cells.

The mechanisms of this tolerance induction are unknown. Using a novel mouse model of inducible TCR stimulation, I was able to isolate memory CD4 T cells to explore the molecular mechanisms that govern memory CD4 T cell apoptosis upon exposure to tolerogenic stimulation. These cells exhibit features of mitochondrial dysfunction, autophagy, metabolism and downstream TCR signalling.

As many target organs in autoimmune diseases in the periphery, it was also important to know whether these same molecular mechanisms of tolerance induction were observable in a peripheral tissue. Using a mouse model of IAV infection I was able to demonstrate a phenotype of partial tolerance within the memory CD4 T cell compartment, where ability to accumulate and provide help to B cells were impaired. Further, altering the inflammatory nature of the subsequent stimulation allowed these cells to overcome the impairments and respond.

Together, these data describe a state of plasticity within the memory CD4 T cell compartment, where tolerance is not fixed but highly regulated to allow memory T cells to survive in conditions of suboptimal stimulation. These data are highly relevant to the development of tolerogenic therapies that aim to dampen memory CD4 T cell responses and the testing of multiple parameters is required to gain full insight into the efficacy of tolerogenic therapy.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: CD4 T cells, memory, tolerance.
Subjects: Q Science > QR Microbiology > QR180 Immunology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Supervisor's Name: MacLeod, Dr. Megan K.L.
Date of Award: 2019
Embargo Date: 11 July 2021
Depositing User: Mr Joshua I Gray
Unique ID: glathesis:2019-74281
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 23 Jul 2019 09:27
Last Modified: 05 Mar 2020 22:14
Thesis DOI: 10.5525/gla.thesis.74281
URI: http://theses.gla.ac.uk/id/eprint/74281
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