CD8+ T CELL RESPONSES TO SIMIAN VIRUS 40 LARGE T ANTIGEN MINIMAL EPITOPES EXPRESSED BY NON-PROFESSIONAL ANTIGEN PRESENTING CELLS
Open Access
- Author:
- Vigliotti, Beth Anne
- Graduate Program:
- Cell and Molecular Biology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- January 30, 2009
- Committee Members:
- Todd Schell, Dissertation Advisor/Co-Advisor
Todd Schell, Committee Chair/Co-Chair
Satvir Singh Tevethia, Committee Member
Mary Judith Tevethia, Committee Member
Robert Harold Bonneau, Committee Member
Hui Ling Chiang, Committee Member - Keywords:
- CD8+ T cell
immunology
cross-presentation
direct-presentation
SV40
large T antigen
minigenes - Abstract:
- In this study we describe a straightforward model that allows for the study of direct-presentation of antigen on transformed non-professional antigen presenting cells (non-pAPCs) in an unmanipulated mouse. While current dogma suggests that pAPCs are necessary to activate naïve CD8+ T cells there is evidence that tumors of non-pAPC origin can also directly activate naïve CD8+ T cells. One of the main problems with identifying the contribution of direct-presentation to the activation of naïve CD8+ T cells is the inability to sequester direct-presentation from cross-presentation. While direct-presentation by antigen expressing cells can be blocked, no effective strategy has been used to target antigen exclusively for the direct-presentation pathway while maintaining an intact immune system. The model antigen used in this study, large T antigen (Tag) from Simian virus 40, is both a known oncoprotein and well-defined tumor antigen. It was found that Tag minimal epitope I and IV are not cross-presented. Therefore, expression of these Tag minimal epitopes in a non-pAPC line allowed for the study of direct-presentation of Tag epitopes in isolation from cross-presentation. The role of direct-presentation was examined in the naïve, activated, and memory CD8+ T cell responses. Naïve CD8+ T cells did not respond to direct-presentation on non-pAPCs while antigen experienced cells did respond to direct-presentation on non-pAPCs, although this response was less efficient than when antigen could also be cross-presented. The roles that costimulation, localization, and short extensions of the minimal epitope had on CD8+ T cell response were also examined. Only the addition of the costimulatory molecule B7.1 enabled naïve CD8+ T cells to respond to direct-presentation on non-pAPCs. These results suggest that pAPCs, which provide both MHCI:peptide presentation and costimulation, are necessary for a CD8+ T cell response to SV40 Tag. While cross-presentation is necessary, a suboptimal CD8+ T cell response developed when cross-presentation on pAPCs was the only source of antigen, however the CD8+ T cell response was recovered when direct-presentation on a non-pAPC was also provided. These results suggest that direct-presentation on non-pAPCs, though not sufficient to trigger a CD8+ T cell response to cell associated antigen is necessary for optimal accumulation of CD8+ T cells.