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Cited by 18Trypanosoma species research and implicationsvaccines and immunoinformatics approachesImmunotherapy and Immune Responses

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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Ersching, Jonatan, Vasconcelos, José R., Ferreira, Camila P., Caetano, Braulia C., Machado, Alexandre V., Bruna–Romero, Oscar, Baron, Monique A., Ferreira, Ludmila R. P. +4 more·2016·PLOS Pathogens
DOI 10.1371/journal.ppat.1005593PMC PMC4851296
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Abstract

The β1i, β2i and β5i 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-γ (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 β1i, β2i and β5i 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-γ+/TNF+) or single-positive (IFN-γ+) 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.

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Authors
Ersching, J., Vasconcelos, J. R., Ferreira, C. P., Caetano, B. C., Machado, A. V., Bruna–Romero, O., Baron, M. A., Ferreira, L. R. P., Cunha-Neto, E., Rock, K. L., Gazzinelli, R. T., & Rodrigues, M. M.
Affiliations
  • Universidade Federal de São Paulo (BR)
  • Fiocruz Minas (BR)
  • Universidade de São Paulo (BR)
  • University of Massachusetts Chan Medical School (US)
  • Universidade Federal de Minas Gerais (BR)
Corresponding author
Gazzinelli, Ricardo T.
ORCID
Venue
PLOS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2016-04-29
Volume
12
Issue
4
Pages
e1005593
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
DOI
10.1371/journal.ppat.1005593
PMC
PMC4851296
OpenAlex
W2343027556
Cited by
18
References
1
Citations by year
2024: 1 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 4
FWCI
2.81
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Pathogens (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by)
  • Arca - Repositório Institucional da Fiocruz (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
Funders
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2010-09361-8, 2013/13668/0, 2009/06820-4, 2012/22514-3, 2015/08814-2)
  • INCTV-CNPq
Topics
  • Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
immunoproteasome, Trypanosoma cruzi, Chagas disease, CD8+ T cell responses, genetic immunization, DNA vaccine, adenovirus vector vaccine, interferon-gamma, TNF-α, MHC class I epitopes, intracellular pathogens
MeSH terms
Adolescent, Adult, Animals, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Humans, Male, Mice, Inbred C57BL, Middle Aged, Trypanosoma cruzi, Chagas Disease, Protozoan Vaccines, Mice, Knockout, CD8-Positive T-Lymphocytes, Proteasome Endopeptidase Complex, Mice, Young Adult, Real-Time Polymerase Chain Reaction

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