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

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dc.citation.issue4
dc.citation.volume12
dc.contributor.authorErsching, Jonatan [UNIFESP]
dc.contributor.authorVasconcelos, Jose Ronnie Carvalho de [UNIFESP]
dc.contributor.authorFerreira, Camila P. [UNIFESP]
dc.contributor.authorCaetano, Braulia C.
dc.contributor.authorMachado, Alexandre V.
dc.contributor.authorBruna-Romero, Oscar
dc.contributor.authorBaron, Monique A.
dc.contributor.authorFerreira, Ludmila R. P.
dc.contributor.authorCunha-Neto, Edecio
dc.contributor.authorRock, Kenneth L.
dc.contributor.authorGazzinelli, Ricardo T.
dc.contributor.authorRodrigues, Mauricio Martins [UNIFESP]
dc.coverageSan Francisco
dc.date.accessioned2020-07-22T13:23:12Z
dc.date.available2020-07-22T13:23:12Z
dc.date.issued2016
dc.description.abstractThe beta 1i, beta 2i and beta 5i 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-gamma (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. cruziinfected beta 1i, beta 2i and beta 5i triple knockout (TKO) mice presented significantly lower frequencies and numbers of splenic CD8(+) effector T cells (CD8(+) CD44(high)CD62L(low)) specific for the previously characterized immunodominant (VNHRFTLV) H-2K(b)-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-gamma(+)/TNF+) or single-positive (IFN-gamma(+)) cells specific for the H-2K(b)-restricted immunodominant as well as subdominant T. cruzi epitopes were higher inWT 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.en
dc.description.affiliationUniv Fed Sao Paulo, Escola Paulista Med, Ctr Terapia Celular & Mol, Sao Paulo, Brazil
dc.description.affiliationUniv Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, Sao Paulo, Brazil
dc.description.affiliationUniv Fed Sao Paulo, Dept Biociencias, Sao Paulo, Brazil
dc.description.affiliationUniv Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA
dc.description.affiliationUniv Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA
dc.description.affiliationFiocruz MS, Ctr Pesquisas Rene Rachou, Belo Horizonte, MG, Brazil
dc.description.affiliationUniv Fed Santa Catarina, Dept Microbiol Imunol & Parasitol, Florianopolis, SC, Brazil
dc.description.affiliationUniv Sao Paulo, Fac Med, Inst Coracao InCor, Sao Paulo, Brazil
dc.description.affiliationUniv Santo Amaro, Sao Paulo, Brazil
dc.description.affiliationUniv Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Imunol, Belo Horizonte, MG, Brazil
dc.description.affiliationWhitehead Inst Biomed Res, Cambridge, MA 02142 USA
dc.description.affiliationUnifespUniv Fed Sao Paulo, Escola Paulista Med, Ctr Terapia Celular & Mol, Sao Paulo, Brazil
dc.description.affiliationUnifespUniv Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, Sao Paulo, Brazil
dc.description.affiliationUnifespUniv Fed Sao Paulo, Dept Biociencias, Sao Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFundacao de Amparo a Pesquisa do Estado de Sao Paulo
dc.description.sponsorshipInstituto Nacional de Ciencia e Tecnologia em Vacina (INCTV-CNPq)
dc.description.sponsorshipCNPq
dc.description.sponsorshipIDFAPESP: 2009/06820-4
dc.description.sponsorshipIDFAPESP: 2010/09361-8
dc.description.sponsorshipIDFAPESP: 2013/13668/0
dc.description.sponsorshipIDFAPESP: 2012/22514-3
dc.description.sponsorshipIDFAPESP: 2012/22514-3
dc.description.sponsorshipIDFAPESP: 2015/08814-2
dc.format.extent-
dc.identifierhttp://dx.doi.org/10.1371/journal.ppat.1005593
dc.identifier.citationPlos Pathogens. San Francisco, v. 12, n. 4, p. -, 2016.
dc.identifier.doi10.1371/journal.ppat.1005593
dc.identifier.fileWOS000378156900063.pdf
dc.identifier.issn1553-7366
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/56086
dc.identifier.wosWOS:000378156900063
dc.language.isoeng
dc.publisherPublic Library Science
dc.relation.ispartofPlos Pathogens
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titleThe 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 cruzien
dc.typeinfo:eu-repo/semantics/article
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