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The Effect of Acute Graft-Versus-Host Disease upon the Peripheral T cell Niche

Evans, Pamela; (2020) The Effect of Acute Graft-Versus-Host Disease upon the Peripheral T cell Niche. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Relapsed disease and infection continue to be the leading causes of treatment failure following allogeneic haematopoietic stem cell transplantation (allo-HSCT). The pathophysiology, common to both, is impaired donor T cell immune reconstitution and/or T cell exhaustion. Therapeutic strategies aimed at improving donor T cell immune reconstitution and preventing T cell exhaustion are required in order to improve patient outcomes. The research presented provides evidence that acute graft-versus-host-disease (aGVHD) impairs T cell recovery and function by damaging the stromal architecture of secondary lymphoid organs. Radio-resistant host non-haematopoietic antigen presenting cells (APCs) are emerging as key players in dictating tissue-specific cytotoxic T lymphocyte (CTL) responses and initiating aGVHD. The fibroblastic reticular cell (FRC) is a subset that plays a central role in every stage of the T cell life cycle in the periphery and is necessary for the generation of protective anti-pathogen immunity. Normally, these cells proliferate and repair the peripheral lymph node following viral damage or hypoxia, by initiating a ‘reorganisational programme’ through interaction with lymphoid tissue inducer (LTi)-like cells, in a mechanism akin to that which occurs during embryogenesis. I show that both the FRC and LTi-like cell populations are targeted by the allogeneic T cell response in aGVHD. Disruption of the FRC-LTi axis results in profound damage to the lymph node structure and persistent hypoplasia of peripheral T cell niches. FRCs are targeted by naïve donor T cells in a CD8⁺ T cell-dependent model of aGVHD, through a mechanism that requires cognate interactions between FRCs and T cells. In contrast to viral infection, lymph nodes in aGVHD are unable to mount a reorganisational programme involving LTi-like cell influx and proliferation. Sustained damage to the FRC network impairs T cell homing to lymph nodes, T cell survival and the capacity to mount a response to 3rd party antigen. These data indicate that future research should focus upon efforts to protect the FRC-LTi axis following transplantation.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The Effect of Acute Graft-Versus-Host Disease upon the Peripheral T cell Niche
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10095669
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