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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.
- Graduation date
- Fall 2019
- Type of Item
- Master of Science
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