Critical contribution of immunoproteasomes in the induction of protective immunity against Trypanosoma cruzi in mice vaccinated with a plasmid encoding a CTL epitope fused to green fluorescence protein.
Acquired immunity against infection with Trypanosoma cruzi is dependent on CD8(+)T cells. Here, to develop a vaccine strategy taking advantage of activated CD8(+)T cells, we constructed a DNA vaccine, designated pGFP-TSA1, encoding a fusion protein linking GFP to a single CTL epitope of TSA1, a leading candidate for vaccine against T. cruzi. C57BL/6 mice vaccinated with this plasmid showed suppressed parasitemia and prolonged survival. Vaccination with pGFP-TSA1 enhanced epitope-specific cytotoxicity and IFN-gamma secretion by CD8(+)T cells. Furthermore, the depletion of CD8(+)T cells prior to challenge infection with T. cruzi completely abolished this protection, indicating that CD8(+)T cells are the principal effector T cells involved. When mice deficient in the proteasome activator PA28alpha/beta or the immunoproteasome subunits LMP2 and LMP7 were used, the protective immunity against infection was profoundly attenuated. Our findings clearly demonstrate that vaccination with pGFP-TSA1 successfully induces protection dependent on CD8(+)T cell activation, in which immunoproteasomes play a crucial role. It is noteworthy to document that physical binding of the epitope and GFP is required for induction of this protection, since mice vaccinated with pTSA1-IRES-GFP failed to acquire resistance, probably because the epitope and GFP are separately expressed in the antigen-presenting cells.
Chou
Bin
B
Department of Parasitology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Hisaeda
Hajime
H
Shen
Jianying
J
Duan
Xuefeng
X
Imai
Takashi
T
Tu
Liping
L
Murata
Shigeo
S
Tanaka
Keiji
K
Himeno
Kunisuke
K
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014355:Chagas Disease / Q000517:prevention & control*; D003546:Cysteine Endopeptidases / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007115:Immunization Schedule; D007271:Injections, Intradermal; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000276:immunology; D010957:Plasmids / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D016052:Protozoan Vaccines / Q000008:administration & dosage*; D016176:T-Lymphocyte Subsets; D013602:T-Lymphocytes, Cytotoxic; D014349:Trypanosoma cruzi / Q000276:immunology*; D014611:Vaccination; D019444:Vaccines, DNA / Q000008:administration & dosage
D018984:Epitopes, T-Lymphocyte; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D016052:Protozoan Vaccines; D019444:Vaccines, DNA; C084839:thymic shared antigen-1; C071313:LMP-2 protein; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex