Immunoproteasome-deficient mice mount largely normal CD8+ T cell responses to lymphocytic choriomeningitis virus infection and DNA vaccination.
During viral infection, constitutive proteasomes are largely replaced by immunoproteasomes, which display distinct cleavage specificities, resulting in different populations of potential CD8(+) T cell epitope peptides. Immunoproteasomes are believed to be important for the generation of many viral CD8(+) T cell epitopes and have been implicated in shaping the immunodominance hierarchies of CD8(+) T cell responses to influenza virus infection. However, it remains unclear whether these conclusions are generally applicable. In this study we investigated the CD8(+) T cell responses to lymphocytic choriomeningitis virus infection and DNA immunization in wild-type mice and in mice lacking the immunoproteasome subunits LMP2 or LMP7. Although the total number of virus-specific cells was lower in LMP2 knockout mice, consistent with their having lower numbers of naive cells before infection, the kinetics of virus clearance were similar in all three mouse strains, and LMP-deficient mice mounted strong primary and secondary lymphocytic choriomeningitis virus-specific CD8(+) T cell responses. Furthermore, the immunodominance hierarchy of the four investigated epitopes (nuclear protein 396 (NP(396)) > gp33 > gp276 > NP(205)) was well maintained. We observed a slight reduction in the NP(205)-specific response in LMP2-deficient mice, but this had no demonstrable biological consequence. DNA vaccination of LMP2- and LMP7-deficient mice induced CD8(+) T cell responses that were slightly lower than, although not significantly different from, those induced in wild-type mice. Taken together, our results challenge the notion that immunoproteasomes are generally needed for effective antiviral CD8(+) T cell responses and for the shaping of immunodominance hierarchies. We conclude that the immunoproteasome may affect T cell responses to only a limited number of viral epitopes, and we propose that its main biological function may lie elsewhere.
Nussbaum
Alexander K
AK
Department of Neuropharmacology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Rodriguez-Carreno
Maria P
MP
Benning
Nicola
N
Botten
Jason
J
Whitton
J Lindsay
JL
D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000821:virology; D003546:Cysteine Endopeptidases / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D004306:Dose-Response Relationship, Immunologic; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology; D018655:Lymphocyte Count; D008216:Lymphocytic Choriomeningitis / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D009698:Nucleoproteins / Q000008:administration & dosage / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D046988:Proteasome Endopeptidase Complex; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology / Q000821:virology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*; D019562:Viral Load
D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D009097:Multienzyme Complexes; D009698:Nucleoproteins; D010446:Peptide Fragments; D019444:Vaccines, DNA; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex