Critical role for the immunoproteasome subunit LMP7 in the resistance of mice to Toxoplasma gondii infection.
Proteasome-mediated proteolysis is responsible for the generation of immunogenic epitopes presented by MHC class I molecules, which activate antigen-specific CD8+ T cells. Immunoproteasomes, defined by the presence of the three catalytic subunits LMP2, MECL-1, and LMP7, have been hypothesized to optimize MHC class I antigen processing. In this study, we demonstrate that the infection of mice with a protozoan parasite, Toxoplasma gondii, induced the expression of LMP7 mRNA in APC and increased the capacity of APC to induce the production of IFN-gamma by antigen-specific CD8+ T cells. In vitro infection of a DC cell line with T. gondii also induced the expression of LMP7 and resulted in enhanced proteasome proteolytic activity. Finally, mice lacking LMP7 were highly susceptible to infection with T. gondii and showed a reduced number of functional CD8+ T cells. These results demonstrate that proteasomes containing LMP7 play an indispensable role in the survival of mice infected with T. gondii, presumably due to the efficient generation of CTL epitopes required for the functional development of CD8+ T cells.
Tu
Liping
L
Department of Parasitology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Moriya
Chikako
C
Imai
Takashi
T
Ishida
Hidekazu
H
Tetsutani
Kohhei
K
Duan
Xuefeng
X
Murata
Shigeo
S
Tanaka
Keiji
K
Shimokawa
Chikako
C
Hisaeda
Hajime
H
Himeno
Kunisuke
K
D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D004790:Enzyme Induction; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014122:Toxoplasma / Q000276:immunology* / Q000502:physiology; D014123:Toxoplasmosis / Q000235:genetics* / Q000276:immunology* / Q000469:parasitology
D009097:Multienzyme Complexes; C071313:LMP-2 protein; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex