Cytotoxic T lymphocytes (CTL) are differentiated CD8+ T cells that eliminate virally infected cells and tumor cells. CTL lyse target cells by at least two distinct mechanisms: degranulation of cytolytic molecules and cell surface expression of Fas ligand (FasL), which induces apoptosis of Fas-expressing target cells. In addition to their defense function, these two cytolytic mechanisms also play crucial roles in homeostatic regulation and contribute to pathogenesis in many different model systems. To fully exploit killer cells in tumor and virus elimination, or dampen the immune response in, for example, autoimmune diseases, it is essential to understand the mechanisms that CTL employ to destroy target cells.
In contrast to the well-characterized degranulation mechanism, the regulation of FasL expression on the CTL cell surface remains elusive and even controversial. The prevailing model at the time I initiated my studies was that FasL is stored in cytolytic granules and that FasL cell surface expression would be subject to the same controls as degranulation. In this thesis, I revealed for the first time that there are two waves of FasL cell surface expression upon target cell engagement, which are differentially regulated by TCR signaling and perform distinct roles in CTL mediated responses. I demonstrated that CTL degranulation and FasL lytic mechanisms are fully independent with respect to stored component localization and regulation. Finally, based on cell fractionation and imaging studies, I suggested that FasL is stored in a recycling endosome associated compartment, which is located in a special niche between the ER and mitochondria and uses a novel microtubule-independent secretory mechanism to translocate to the cell surface. Together, these findings provide important insight into the regulation and role of FasL in CTL mediated responses. / Immunology
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/559 |
| Date | 11 1900 |
| Creators | He, Jinshu |
| Contributors | Ostergaard, Hanne (Medical Microbiology and Immunology), Barry, Michele (Medical Microbiology and Immunology), Lacy, Paige (Medicine), Bleackley, R. Chris (Biochemistry), Watts, Tania (Immunology, University of Toronto) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
| Format | 22299080 bytes, application/pdf |
| Relation | He, Jin-Shu & Ostergaard, Hanne L. (2007). Journal of Immunology. http://www.jimmunol.org/cgi/content/full/179/4/2339 |
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