Immunodominance of an antiviral cytotoxic T cell response is shaped by the kinetics of viral protein expression.
Lymphocytic choriomeningitis virus (LCMV) infection induces a protective CTL response consisting of gp- and nucleoprotein (NP)-specific CTL. We find that a small load of LCMV led to immunodominance of NP-CTL, whereas a large viral load resulted in dominance of gp-CTL. This is the first study describing that immunodominance is not fixed after infection with a given pathogen, but varies with the viral load instead. We assumed higher Ag sensitivity for NP-CTL, which would explain their preferential priming at low viral load, as well as their overstimulation resulting in selective exhaustion at high viral load. The higher Ag sensitivity of NP-CTL was due to faster kinetics of NP-epitope presentation. Thus, we uncover a novel factor that impinges upon immunodominance and is related to the kinetics of virus protein expression. We propose that CTL against early viral proteins swiftly interfere with virus replication, resulting in efficient protection. If these "early" CTL fail in immediate virus control, they are activated in the face of higher viral load compared with "late" CTL and are therefore prone to be exhausted. Thus, the observed absence of early CTL in persistent infections might not be the cause, but rather the consequence of viral persistence.
Probst
Hans Christian
HC
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Tschannen
Kathrin
K
Gallimore
Awen
A
Martinic
Marianne
M
Basler
Michael
M
Dumrese
Tilman
T
Jones
Emma
E
van den Broek
Maries F
MF
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism; D016056:Immunodominant Epitopes / Q000276:immunology* / Q000378:metabolism; D007700:Kinetics; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009698:Nucleoproteins / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D019562:Viral Load; D014764:Viral Proteins / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D016056:Immunodominant Epitopes; D009698:Nucleoproteins; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins