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

  • T cell
  • PD-1
  • Tolerance

• Graduation date

  Fall 2019

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-was0-xe65

• License

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