The antiviral immune response in mice devoid of immunoproteasome activity.
The replacement of the catalytically active proteasome subunits β1, β2, and β5 by the immunoproteasome subunits low molecular mass polypeptide (LMP) 2 (β1i), multicatalytic endopeptidase complex-like-1 (MECL-1) (β2i), and LMP7 (β5i) is required for the production of numerous class I ligands. Hitherto, investigation of the immunoproteasome was confined to the analysis of mice deficient for one or two immunosubunits. In this study, we characterized LMP2(-/-)/MECL-1(-/-) double-deficient mice and used the well-defined LMP7-selective inhibitor ONX 0914 in these mice to generate mice lacking the activity of all immunoproteasome subunits. LMP2(-/-)/MECL-1(-/-) double-deficient mice had strongly reduced numbers of CD8(+) T cells in the spleen. Nevertheless, infection with the lymphocytic choriomeningits virus induced a normal cytotoxic T cell response in these mice, although the T cell response to several class I epitopes was altered. Treatment of LMP2(-/-)/MECL-1(-/-) double-deficient mice with the LMP7-selective inhibitor ONX 0914 elicited a strong CTL response in lymphocytic choriomeningitis virus-infected mice. Thereby, the T(CD8+) response to nucleoprotein 205-212, which is barely detectable in LMP2(-/-)/MECL-1(-/-) double-deficient mice, could be reverted to normal levels by LMP7 inhibition. Additional experiments could demonstrate that the increased CTL response to the nucleoprotein 205-212 in mice lacking functional immunoproteasome is due to an altered class I presentation of this epitope. Taken together, to our knowledge, this is the first study investigating viral infection in mice lacking activity of all three immunoproteasome subunits.
Biotechnology Institute Thurgau at Constance University, CH-8280 Kreuzlingen, Switzerland. Michael.Basler@uni-konstanz.de
Michael
M
Basler
Ulrike
U
Beck
Christopher J
CJ
Kirk
Marcus
M
Groettrup
D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology*; D015153:Blotting, Western; D002469:Cell Separation; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000276:immunology*; D005434:Flow Cytometry; D008213:Lymphocyte Activation / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009698:Nucleoproteins / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000172:deficiency / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D009698:Nucleoproteins; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex; C490920:Psmb10 protein, mouse