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

PLoS Pathogens

Oscar Bruna–Romero¹  Jonatan Ersching²  José R. Vasconcelos²  Braulia C. Caetano²  Camila P. Ferreira³  Monique A. Baron⁴  Alexandre V. Machado⁵  Maurício M. Rodrigues⁵  Ricardo T. Gazzinelli⁶  Ludmila R. P. Ferreira⁶  Edécio Cunha-Neto⁶  Kenneth L. Rock⁷ 

[1] Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil;Centro de Terapia Celular e Molecular and Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo - Escola Paulista de Medicina, São Paulo, São Paulo, Brazil;Departamento de Biociências, Universidade Federal de São Paulo, Santos, São Paulo, Brazil;Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil;Departments of Medicine and Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America;Instituto do Coração (InCor), Faculdade de Medicina - Universidade de São Paulo, São Paulo, São Paulo, Brazil;Universidade Santo Amaro, São Paulo, São Paulo, Brazil

关键词: Cytotoxic T cells;    T cells;    Trypanosoma cruzi;    Parasitic diseases;    Cell staining;    Major histocompatibility complex;    Spleen;    Immune response;   

DOI  :  10.1371/journal.ppat.1005593

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY