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Investigating the role of PD-1 in T cell tolerance

  • Author / Creator
    Kelly, Rees G
  • T cells are a vital part of the adaptive immune system that function to eliminate foreign threats while remaining tolerant to healthy-self. During T cell development in the thymus, T cells are generated with various T cell receptor (TCR) specificities, such that they can respond to a near endless variety of threats. However, some T cells deleteriously generate a TCR specific for self and thus, have the potential to induce autoimmune
    disease. To prevent this, self-reactive thymocytes undergo negative selection after receiving a high affinity signal in the thymus. T cells are negatively selected against ubiquitous antigen (UbA) in the thymic cortex or tissue restricted antigen (TRA) in the thymic medulla. Various molecular factors are differentially important for ensuring self-tolerance to either UbA or TRA; one such protein is programmed cell death protein 1 (PD-1).

    Given that our group has previously investigated the role of PD-1 in T cell tolerance to UbA, we used the OT-I TCR transgenic mouse model to investigate the role of PD-1 in T cell tolerance to TRA. We determined that CD8+ T cells from OT-I Bim-/- >
    RIP-mOVA bone marrow chimeras were intrinsically impaired but were not functionally rescued by blocking PD-1 signalling in vitro. Subsequently, we generated OT-I PD-1-/- > RIP-mOVA chimeras and found that 100% of OT-I PD-1-/- > RIP-mOVA chimeras develop autoimmunity, compared to 0% of control OT-I WT > RIP-mOVA controls. We then isolated OT-I PD-1-/- T cells from the thymus of OT-I PD-1-/- > RIP-mOVA chimeras and found that clonal deletion was intact, suggesting that PD-1 signals impact T cell tolerance outside of deletional mechanisms. In the periphery, we found a greater number of CD8+ T cells from OT-I PD-1-/- > RIP-mOVA chimeras compared to OT-I WT > RIP-mOVA controls, and these cells exhibited differences in proliferation capacity, trafficking potential and cytokine production. Collectively, this data suggests that PD-1 plays a significant role in establishing T cell tolerance to TRA via non-deletional tolerance mechanisms.

  • Subjects / Keywords
  • Graduation date
    Fall 2019
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/r3-was0-xe65
  • License
    Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.