The involvement of immunoproteasomes in induction of MHC class I-restricted immunity targeting Toxoplasma SAG1.
The ubiquitin-proteasome system (UPS) plays an indispensable role in inducing MHC class I-restricted CD8+ T cells and was exploited in the development of a DNA vaccine against the intracellular protozoan Toxoplasma gondii by constructing a chimeric DNA encoding a fusion protein between murine ubiquitin and the toxoplasma antigen SAG1. The SAG1 peptide was promptly degraded in antigen-presenting cells (APCs) transfected with the chimeric DNA. Degradation, however, was hampered by incubating the APCs with the proteasome inhibitor epoxomicin. Mice vaccinated with the DNA acquired potent protective immunity mediated by MHC class I-restricted CD8+ T cells against infection by the highly virulent Toxoplasma. The accelerated degradation and induction of immunity were dependent on the UPS since mice lacking an immuno-subunit of 20S proteasome, LMP7, lost these functions, although they were independent of the proteasome regulator PA28alpha/beta complex.
Ishii
Kazunari
K
Department of Parasitology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Hisaeda
Hajime
H
Duan
Xuefeng
X
Imai
Takashi
T
Sakai
Tohru
T
Fehling
Hans Jörg
HJ
Murata
Shigeo
S
Chiba
Tomoki
T
Tanaka
Keiji
K
Hamano
Shinjiro
S
Sano
Miyuki
M
Yano
Akihiko
A
Himeno
Kunisuke
K
D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology* / Q000378:metabolism; D019470:Biolistics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007115:Immunization Schedule; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D011506:Proteins / Q000235:genetics / Q000276:immunology; D015800:Protozoan Proteins / Q000276:immunology* / Q000378:metabolism; D016052:Protozoan Vaccines / Q000008:administration & dosage*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D037182:T-Cell Antigen Receptor Specificity; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology / Q000517:prevention & control*; D025801:Ubiquitin / Q000276:immunology* / Q000378:metabolism; D019444:Vaccines, DNA / Q000008:administration & dosage
D000953:Antigens, Protozoan; D015395:Histocompatibility Antigens Class I; D009097:Multienzyme Complexes; D011506:Proteins; D015800:Protozoan Proteins; D016052:Protozoan Vaccines; D011993:Recombinant Fusion Proteins; C047168:SAG1 antigen, Toxoplasma; D025801:Ubiquitin; D019444:Vaccines, DNA; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex; C486213:Psme1 protein, mouse; C486214:Psme2 protein, mouse