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.contributor.author Ersching, Jonatan [UNIFESP]
dc.contributor.author Vasconcelos, Jose Ronnie Carvalho de [UNIFESP]
dc.contributor.author Ferreira, Camila P. [UNIFESP]
dc.contributor.author Caetano, Braulia C.
dc.contributor.author Machado, Alexandre V.
dc.contributor.author Bruna-Romero, Oscar
dc.contributor.author Baron, Monique A.
dc.contributor.author Ferreira, Ludmila R. P.
dc.contributor.author Cunha-Neto, Edecio
dc.contributor.author Rock, Kenneth L.
dc.contributor.author Gazzinelli, Ricardo T.
dc.contributor.author Rodrigues, Mauricio Martins [UNIFESP]
dc.date.accessioned 2020-07-22T13:23:12Z
dc.date.available 2020-07-22T13:23:12Z
dc.date.issued 2016
dc.identifier http://dx.doi.org/10.1371/journal.ppat.1005593
dc.identifier.citation Plos Pathogens. San Francisco, v. 12, n. 4, p. -, 2016.
dc.identifier.issn 1553-7366
dc.identifier.uri https://repositorio.unifesp.br/handle/11600/56086
dc.description.abstract The 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.sponsorship Fundacao de Amparo a Pesquisa do Estado de Sao Paulo
dc.description.sponsorship Instituto Nacional de Ciencia e Tecnologia em Vacina (INCTV-CNPq)
dc.description.sponsorship CNPq
dc.format.extent -
dc.language.iso eng
dc.publisher Public Library Science
dc.relation.ispartof Plos Pathogens
dc.rights Acesso aberto
dc.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 en
dc.type Artigo
dc.description.affiliation Univ Fed Sao Paulo, Escola Paulista Med, Ctr Terapia Celular & Mol, Sao Paulo, Brazil
dc.description.affiliation Univ Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, Sao Paulo, Brazil
dc.description.affiliation Univ Fed Sao Paulo, Dept Biociencias, Sao Paulo, Brazil
dc.description.affiliation Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA
dc.description.affiliation Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA
dc.description.affiliation Fiocruz MS, Ctr Pesquisas Rene Rachou, Belo Horizonte, MG, Brazil
dc.description.affiliation Univ Fed Santa Catarina, Dept Microbiol Imunol & Parasitol, Florianopolis, SC, Brazil
dc.description.affiliation Univ Sao Paulo, Fac Med, Inst Coracao InCor, Sao Paulo, Brazil
dc.description.affiliation Univ Santo Amaro, Sao Paulo, Brazil
dc.description.affiliation Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Imunol, Belo Horizonte, MG, Brazil
dc.description.affiliation Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
dc.description.affiliationUnifesp Univ Fed Sao Paulo, Escola Paulista Med, Ctr Terapia Celular & Mol, Sao Paulo, Brazil
dc.description.affiliationUnifesp Univ Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, Sao Paulo, Brazil
dc.description.affiliationUnifesp Univ Fed Sao Paulo, Dept Biociencias, Sao Paulo, Brazil
dc.description.sponsorshipID FAPESP: 2009/06820-4
dc.description.sponsorshipID FAPESP: 2010/09361-8
dc.description.sponsorshipID FAPESP: 2013/13668/0
dc.description.sponsorshipID FAPESP: 2012/22514-3
dc.description.sponsorshipID FAPESP: 2012/22514-3
dc.description.sponsorshipID FAPESP: 2015/08814-2
dc.identifier.file WOS000378156900063.pdf
dc.identifier.doi 10.1371/journal.ppat.1005593
dc.description.source Web of Science
dc.identifier.wos WOS:000378156900063
dc.coverage San Francisco
dc.citation.volume 12
dc.citation.issue 4



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