Detailed project information
| Title | : | EFFECTS OF EARLY ANTIGEN PROCESSING KINETICS ON cd8 t CELL PRIMING |
| Applicant | : | Prof. dr. A.W.C.A. Cornelissen |
| Research institute | : | Universiteit Utrecht Faculteit Diergeneeskunde Departement Infectieziekten en Immunologie |
| Team members | : | Dr. E.J.A.M. Sijts |
| Location | : | no information available |
| Duration | : | 10/01/2005 tot 01/20/2010 |
| Strategic goal | : | Talent |
| Budget | : | Eur 155,690.00 personnel Eur 29,000.00 equipment |
| Subsidy | : | More Women Researchers as University Lecturers (MEERVOUD) |
peptides by MHC class I molecules on the surface of professional antigen presenting cells
(pAPC). These peptides are generated upon intracellular degradation of pathogen-derived
proteins by cellular proteasomes. pAPC and IFNã-exposed cells express three inducible
"immuno"subunits which modify the catalytic activity of proteasomes and accelerate the
generation of many immunodominant peptides. Here, we propose that immunoproteasomegenerated
peptides are the prime-target of pathogen-specific CD8 T-cell responses due to the fact
that these antigenic peptides appear the earliest on the cell surface of pAPC following infection.
Consequently, such peptides are the most potent in inducing CD8 T-cell responses. We will test
this hypothesis by infecting normal and genetically modified mice that lack the inducible
proteasome components with recombinant Listeria monocytogenes. CD8 T-cell responses to a
range of rapidly and slowly degraded Listeria antigens and to rapidly and slowly generated
Listeria peptides will be examined. Our studies will show whether the relative rates with which
antigenic peptides are generated determine their capacity to prime CD8 T-cell responses.
Furthermore, we will determine in which cells the pAPC-presented peptides are processed. Mice
that express the inducible proteasome components in specific cell types only will be generated
and tested for their ability to mount responses to peptides that are inefficiently generated by the
unmodified type of proteasome. These experiments will reveal whether antigen-processing events
in infected cells or in cross-presenting pAPC, and in which pAPC, are decisive for the priming of
CD8 T-cell responses.
Articles
- (2007). Kinetics of processing determine the immunogenicity of immunoproteasome-generated epitopes. J Immunol. pp. 7557-7562
- (2008). The proteasome immunosubunit MECL-1 is a T cell intrinsic factor influencing homeostatic expansion. Infect Immun. pp. 1207-1213
