title: The Combined Deficiency of Immunoproteasome Subunits Affects Both the Magnitude and Quality of Pathogen- and Genetic Vaccination-Induced CD8+ T Cell Responses to the Human Protozoan Parasite Trypanosoma cruzi.
abstract: The β1i, β2i and β5i immunoproteasome subunits have an important role in defining the repertoire of MHC class I-restricted epitopes. However, the impact of combined deficiency of the three immunoproteasome subunits in the development of protective immunity to intracellular pathogens has not been investigated. Here, we demonstrate that immunoproteasomes play a key role in host resistance and genetic vaccination-induced protection against the human pathogen Trypanosoma cruzi (the causative agent of Chagas disease), immunity to which is dependent on CD8+ T cells and IFN-γ (the classical immunoproteasome inducer). We observed that infection with T. cruzi triggers the transcription of immunoproteasome genes, both in mice and humans. Importantly, genetically vaccinated or T. cruzi-infected β1i, β2i and β5i triple knockout (TKO) mice presented significantly lower frequencies and numbers of splenic CD8+ effector T cells (CD8+CD44highCD62Llow) specific for the previously characterized immunodominant (VNHRFTLV) H-2Kb-restricted T. cruzi epitope. Not only the quantity, but also the quality of parasite-specific CD8+ T cell responses was altered in TKO mice. Hence, the frequency of double-positive (IFN-γ+/TNF+) or single-positive (IFN-γ+) cells specific for the H-2Kb-restricted immunodominant as well as subdominant T. cruzi epitopes were higher in WT mice, whereas TNF single-positive cells prevailed among CD8+ T cells from TKO mice. Contrasting with their WT counterparts, TKO animals were also lethally susceptible to T. cruzi challenge, even after an otherwise protective vaccination with DNA and adenoviral vectors. We conclude that the immunoproteasome subunits are key determinants in host resistance to T. cruzi infection by influencing both the magnitude and quality of CD8+ T cell responses.
authors.affiliation: Centro de Terapia Celular e Molecular and Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo - Escola Paulista de Medicina, São Paulo, São Paulo, Brazil.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Ersching
authors.affiliation: Centro de Terapia Celular e Molecular and Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo - Escola Paulista de Medicina, São Paulo, São Paulo, Brazil.|Departamento de Biociências, Universidade Federal de São Paulo, Santos, São Paulo, Brazil.
authors.forename: José R
authors.initials: JR
authors.lastname: Vasconcelos
authors.affiliation: Centro de Terapia Celular e Molecular and Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo - Escola Paulista de Medicina, São Paulo, São Paulo, Brazil.
authors.forename: Camila P
authors.initials: CP
authors.lastname: Ferreira
authors.affiliation: Departments of Medicine and Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Braulia C
authors.initials: BC
authors.lastname: Caetano
authors.affiliation: Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Alexandre V
authors.initials: AV
authors.lastname: Machado
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: Oscar
authors.initials: O
authors.lastname: Bruna-Romero
authors.affiliation: Instituto do Coração (InCor), Faculdade de Medicina - Universidade de São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Monique A
authors.initials: MA
authors.lastname: Baron
authors.affiliation: Instituto do Coração (InCor), Faculdade de Medicina - Universidade de São Paulo, São Paulo, São Paulo, Brazil.|Universidade Santo Amaro, São Paulo, São Paulo, Brazil.
authors.forename: Ludmila R P
authors.initials: LR
authors.lastname: Ferreira
authors.affiliation: Instituto do Coração (InCor), Faculdade de Medicina - Universidade de São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Edécio
authors.initials: E
authors.lastname: Cunha-Neto
authors.affiliation: Departments of Medicine and Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Rock
authors.affiliation: Departments of Medicine and Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.|Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil.|Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Ricardo T
authors.initials: RT
authors.lastname: Gazzinelli
authors.affiliation: Centro de Terapia Celular e Molecular and Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo - Escola Paulista de Medicina, São Paulo, São Paulo, Brazil.
authors.forename: Maurício M
authors.initials: MM
authors.lastname: Rodrigues
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D014355:Chagas Disease / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D046988:Proteasome Endopeptidase Complex / Q000276:immunology*; D016052:Protozoan Vaccines / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D014349:Trypanosoma cruzi; D055815:Young Adult
chemical_list: D016052:Protozoan Vaccines; D046988:Proteasome Endopeptidase Complex