Requirement for IL-2-receptor and B7/CD28 signaling in cytotoxic T cells.
| dc.contributor.author | Makrigiannis, Andrew Peter. | en_US |
| dc.contributor.degree | Ph.D. | en_US |
| dc.date.accessioned | 2014-10-21T12:38:18Z | |
| dc.date.available | 1998 | |
| dc.date.issued | 1998 | en_US |
| dc.description | In order for cytolytic T lymphocytes (CTL) to achieve optimal activation they must receive a variety of signals. These signals can be provided by cytokines, as well as by cell surface proteins present on antigen presenting cells. Signaling through the IL-2R of CTL is important for the induction of cytolytic gene expression and the acquisition of cytotoxicity. Rapamycin (RAP) is a drug which can inhibit the p70s6k pathway of IL-2R signal transduction. I have shown that RAP inhibits proliferation, cytotoxicity, granzyme B (Gzm B), and perforin gene expression in CTL induced with anti-CD3 mAb. Treatment with RAP plus rIL-2 was able to restore proliferation and cytolytic gene expression, but not cytotoxicity to control levels. This suggests that RAP-sensitive rather than RAP-resistant IL-2R signaling pathways are required for the acquisition of cytotoxicity. In addition to signaling through the IL-2R, anti-CD3-activated CTL also require CD28-derived costimulatory signals. Using blocking mAb specific for B7-1 and B7-2, I found that B7-2 is the major ligand for CD28 during anti-CD3 activation of CTL. On the other hand, B7-1-mediated costimulation is a very minor component. While B7-2 was expressed on both T and B cells, T cell-derived B7-2 did not contribute to costimulation. Blockade of B7-2/CD28 interactions led to decreased production of IL-2, IL-4, IL-6, IL-10, and IFN-gamma, as well as decreased expression of Gzm B. Exogenous rIL-2 and IL-12 were found to substitute for B7-2 costimulation, restoring cytolytic activity and Gzm B expression to control levels. IL-12-mediated costimulation was found to be IL-2-dependent and IFN-gamma-independent. In conclusion, these results indicate that RAP would be an effective therapy in pathologies mediated by the granule exocytosis pathway of CTL. In addition, B7-2 is the major costimulator for anti-CD3-induced CTL activation, suggesting that CTL activation in vivo may utilize this CD28 ligand. | en_US |
| dc.description | Thesis (Ph.D.)--Dalhousie University (Canada), 1998. | en_US |
| dc.identifier.other | AAINQ36589 | en_US |
| dc.identifier.uri | http://hdl.handle.net/10222/55602 | |
| dc.language | eng | en_US |
| dc.publisher | Dalhousie University | en_US |
| dc.publisher | en_US | |
| dc.subject | Biology, Molecular. | en_US |
| dc.subject | Biology, Cell. | en_US |
| dc.subject | Health Sciences, Immunology. | en_US |
| dc.title | Requirement for IL-2-receptor and B7/CD28 signaling in cytotoxic T cells. | en_US |
| dc.type | text | en_US |
Files
Original bundle
1 - 1 of 1
Loading...
- Name:
- NQ36589Redacted.pdf
- Size:
- 8.35 MB
- Format:
- Adobe Portable Document Format
- Description: