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

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

Author Ersching, Jonatan Autor UNIFESP Google Scholar
Vasconcelos, Jose Ronnie Carvalho de Autor UNIFESP Google Scholar
Ferreira, Camila P. Autor UNIFESP Google Scholar
Caetano, Braulia C. Google Scholar
Machado, Alexandre V. Google Scholar
Bruna-Romero, Oscar Google Scholar
Baron, Monique A. Google Scholar
Ferreira, Ludmila R. P. Google Scholar
Cunha-Neto, Edecio Google Scholar
Rock, Kenneth L. Google Scholar
Gazzinelli, Ricardo T. Google Scholar
Rodrigues, Mauricio Martins Autor UNIFESP Google Scholar
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.
xmlui.dri2xhtml.METS-1.0.item-coverage San Francisco
Language English
Sponsor Fundacao de Amparo a Pesquisa do Estado de Sao Paulo
Instituto Nacional de Ciencia e Tecnologia em Vacina (INCTV-CNPq)
CNPq
Grant number FAPESP: 2009/06820-4
FAPESP: 2010/09361-8
FAPESP: 2013/13668/0
FAPESP: 2012/22514-3
FAPESP: 2012/22514-3
FAPESP: 2015/08814-2
Date 2016
Published in Plos Pathogens. San Francisco, v. 12, n. 4, p. -, 2016.
ISSN 1553-7366 (Sherpa/Romeo, impact factor)
Publisher Public Library Science
Extent -
Origin http://dx.doi.org/10.1371/journal.ppat.1005593
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000378156900063
URI https://repositorio.unifesp.br/handle/11600/56086

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