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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

Ersching, Jonatan ; Vasconcelos, José R ; Ferreira, Camila P ; Caetano, Braulia C ; Machado, Alexandre V ; Bruna-Romero, Oscar ; Baron, Monique A ; Ferreira, Ludmila R P ; Cunha-Neto, Edécio ; Rock, Kenneth L ; Gazzinelli, Ricardo T ; Rodrigues, Maurício M Müller, Ingrid

PLoS pathogens, 2016-04, Vol.12 (4), p.e1005593-e1005593 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
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
Autor: Ersching, Jonatan ; Vasconcelos, José R ; Ferreira, Camila P ; Caetano, Braulia C ; Machado, Alexandre V ; Bruna-Romero, Oscar ; Baron, Monique A ; Ferreira, Ludmila R P ; Cunha-Neto, Edécio ; Rock, Kenneth L ; Gazzinelli, Ricardo T ; Rodrigues, Maurício M
Müller, Ingrid
Assuntos: Adolescent ; Adult ; Animals ; Biology and life sciences ; CD8-Positive T-Lymphocytes - immunology ; Chagas Disease - immunology ; Deoxyribonucleic acid ; DNA ; Enzyme-Linked Immunosorbent Assay ; Female ; Flow Cytometry ; Funding ; Humans ; Infections ; Lymphocytes ; Male ; Medicine and health sciences ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Middle Aged ; Mortality ; Parasites ; Proteasome Endopeptidase Complex - immunology ; Protozoa ; Protozoan Vaccines - immunology ; Quality ; Real-Time Polymerase Chain Reaction ; Research and Analysis Methods ; Rodents ; Trypanosoma cruzi ; Vaccines ; Young Adult
É parte de: PLoS pathogens, 2016-04, Vol.12 (4), p.e1005593-e1005593
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Conceived and designed the experiments: JE BCC KLR RTG MMR. Performed the experiments: JE CPF. Analyzed the data: JE JRV KLR RTG MMR. Contributed reagents/materials/analysis tools: ECN MAB LRPF AVM OBR KLR RTG. Wrote the paper: JE RTG MMR.
I have read the journal's policy and the authors of this manuscript have the following competing interests: RTG, MMR, AVM and OBR. are named inventors on patent applications covering Trypanosoma cruzi vectored vaccines and immunization regimens.This does not alter our adherence to all PLOS policies on sharing data and materials.
Current address: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America
Descrição: 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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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

Ersching, Jonatan ; Vasconcelos, José R ; Ferreira, Camila P ; Caetano, Braulia C ; Machado, Alexandre V ; Bruna-Romero, Oscar ; Baron, Monique A ; Ferreira, Ludmila R P ; Cunha-Neto, Edécio ; Rock, Kenneth L ; Gazzinelli, Ricardo T ; Rodrigues, Maurício M Müller, Ingrid

United States: Public Library of Science

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