Antigen Processing and Presentation: Contributions of the Cross-Presentation Pathway in Eliciting CD8+ T cell Responses In Vivo
Open Access
- Author:
- Tewalt , Eric Franklin
- Graduate Program:
- Immunology and Infectious Diseases
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- November 04, 2008
- Committee Members:
- Christopher Charles Norbury, Dissertation Advisor/Co-Advisor
Christopher Charles Norbury, Committee Chair/Co-Chair
Avery August, Committee Member
Todd Schell, Committee Member
Neil David Christensen, Committee Member
Ralph Lauren Keil, Committee Member - Keywords:
- Scavenger Receptor
Cross-presentation
Vaccinia Virus
T cells
gp96
Dendritic Cell - Abstract:
- CD8+ T cells (TCD8+) are activated by peptide-MHC (pMHC) Class I complexes presented on the surface of professional antigen presenting cells (pAPC). Antigenic pMHC-I can be generated from two spatially distinct sources. The direct presentation pathway involves generation of peptide from protein substrate synthesized within the cell that is presenting the pMHC-I. When direct presentation is blocked, the cross-presentation pathway, in which antigen is transferred from donor cells to uninfected pAPC, is thought to compensate and allow the generation of effector TCD8+. The mechanisms by which cross presentation of exogenous antigens occur in vivo remain controversial. The objective of this thesis, therefore, has been to expand our knowledge of the mechanisms of cross presentation in vivo for subsequent TCD8+ activation. The C-type lectin, Scavenger Receptor-A (SR-A), has been implicated in a number of potential cross presentation pathways, including the presentation of peptide bound to heat shock proteins and the transfer of pMHC-I from donor cells to pAPC. We demonstrate that initiation of TCD8+ responses is normal in mice lacking SR-A, and that the redundancy of ligand binding exhibited by the SR family is likely an important mechanism that ensures cross presentation in vivo. These observations emphasize the requirement to target multiple receptors and antigen processing pathways during the rational design of vaccines aimed at eliciting protective TCD8+. Further, we demonstrate that late Vaccinia virus (VACV) antigens do not enter the cross-presentation pathway, even when identical antigens driven by early promoters access this pathway efficiently. The mechanism mediating this novel means of viral modulation of antigen presentation involves the sequestration of late antigens within virus factories. Early antigens and cellular antigens are cross-presented from virus-infected cells, as are late antigens that are targeted to compartments outside of the virus factories. This virus-mediated blockade specifically targets the cross-presentation pathway, as late antigen that is not cross-presented efficiently enters the MHC Class II pathway. VACV, therefore, has evolved a mechanism to specifically inhibit the cross-presentation pathway within pAPCs following internalization of exogenous VACV late promoter-driven antigen. Thus, we have demonstrated for the first time pathogen-mediated modulation of the cross-presentation pathway.