In accordance with the two-signal model, optimal T cell activation can only occur in the presence of a primary antigen specific signal, provided by the T cell receptor, and a second co-stimulatory signal. The most potent co-stimulatory molecules identified to date are the CD28/CTLA-4 receptors with their CD80/CD86 ligands, found on T cells and antigen presenting cells (APC) respectively. Many studies have implicated the V-domain of CD80 and CD86 to be responsible for the direct interaction with CD28/CTLA-4. Conversely, few studies have shown that the C-domain CD80 is crucial for the interaction and ultimate suppression of T cell activation and proliferation by binding to CTLA4. The thesis herein identifies amino acids located in the C-domain of CD80 that proves critical for the binding of CTLA-4. This particular mutant, N5-6, exhibits a preferential binding to CTLA-4. We observe 7-fold enhanced binding to CTLA-4 while maintaining its conventional binding to CD28. Functionally, this mutant is still capable of activating T cells via CD28. Interestingly, binding to CD28 is not inhibited by the presence of soluble CTLA-4 as a competitive inhibitor despite its greater affinity. As a DNA vaccine, this mutant, along with other mutants exhibiting differential binding to CD28/CTLA-4, can be used as a means modulate T cell responses. This can provide a therapeutic approach to the treatment of autoimmunity or aid in the eradication of reservoir cells in HIV and HSV infections.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.80870 |
| Date | January 2003 |
| Creators | Saba, Nicole |
| Contributors | Sekaly, Rafick-Pierre (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Microbiology and Immunology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002031516, proquestno: AAIMQ98735, Theses scanned by UMI/ProQuest. |
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