| 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. |
