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dc.contributor.authorErsching, Jonatan
dc.contributor.authorVasconcelos, Jose Ronnie
dc.contributor.authorFerreira, Camila P.
dc.contributor.authorCaetano, Braulia C.
dc.contributor.authorMachado, Alexandre Vieira
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
dc.date2022-08-11T08:09:45.000
dc.date.accessioned2022-08-23T16:42:20Z
dc.date.available2022-08-23T16:42:20Z
dc.date.issued2016-04-29
dc.date.submitted2016-10-05
dc.identifier.citationPLoS Pathog. 2016 Apr 29;12(4):e1005593. doi: 10.1371/journal.ppat.1005593. eCollection 2016. <a href="http://dx.doi.org/10.1371/journal.ppat.1005593">Link to article on publisher's site</a>
dc.identifier.issn1553-7366 (Linking)
dc.identifier.doi10.1371/journal.ppat.1005593
dc.identifier.pmid27128676
dc.identifier.urihttp://hdl.handle.net/20.500.14038/40071
dc.description.abstractThe beta1i, beta2i and beta5i 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. cruzi-infected beta1i, beta2i and beta5i 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-gamma+/TNF+) or single-positive (IFN-gamma+) 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=27128676&dopt=Abstract">Link to Article in PubMed</a>
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectImmunity
dc.subjectImmunopathology
dc.subjectImmunoprophylaxis and Therapy
dc.subjectParasitic Diseases
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 cruzi
dc.typeJournal Article
dc.source.journaltitlePLoS pathogens
dc.source.volume12
dc.source.issue4
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3880&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/2875
dc.identifier.contextkey9233097
refterms.dateFOA2022-08-23T16:42:20Z
html.description.abstract<p>The beta1i, beta2i and beta5i 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. cruzi-infected beta1i, beta2i and beta5i 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-gamma+/TNF+) or single-positive (IFN-gamma+) 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.</p>
dc.identifier.submissionpathoapubs/2875
dc.contributor.departmentDepartment of Pathology
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.source.pagese1005593


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