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
Authors
Ersching, JonatanVasconcelos, Jose Ronnie
Ferreira, Camila P.
Caetano, Braulia C.
Machado, Alexandre Vieira
Bruna-Romero, Oscar
Baron, Monique A.
Ferreira, Ludmila R.P.
Cunha-Neto, Edecio
Rock, Kenneth L.
Gazzinelli, Ricardo T.
Rodrigues, Mauricio Martins
UMass Chan Affiliations
Department of PathologyDepartment of Medicine, Division of Infectious Diseases and Immunology
Document Type
Journal ArticlePublication Date
2016-04-29
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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.Source
PLoS Pathog. 2016 Apr 29;12(4):e1005593. doi: 10.1371/journal.ppat.1005593. eCollection 2016. Link to article on publisher's siteDOI
10.1371/journal.ppat.1005593Permanent Link to this Item
http://hdl.handle.net/20.500.14038/40071PubMed ID
27128676Related Resources
Link to Article in PubMedDistribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1371/journal.ppat.1005593
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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/