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 ^{[1, 2, 3]} ; Vasconcelos, Jose R. ^{[1, 4, 3]} ; Ferreira, Camila P. ^{[1, 3]} ; Caetano, Braulia C. ^{[5, 6]} ; Machado, Alexandre V. ^[7] ; Bruna-Romero, Oscar ^[8] ; Baron, Monique A. ^[9] ; Ferreira, Ludmila R. P. ^{[10, 9]} ; Cunha-Neto, Edecio ^[9] ; Rock, Kenneth L. ^{[5, 6]} ; Gazzinelli, Ricardo T. ^{[11, 7, 5, 6]} ; Rodrigues, Maurcio M. ^{[1, 3]}

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^[1] Univ Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, Sao Paulo - Brazil

^[2] Whitehead Inst Biomed Res, Cambridge, MA 02142 - USA

^[3] Univ Fed Sao Paulo, Escola Paulista Med, Ctr Terapia Celular & Mol, Sao Paulo - Brazil

^[4] Univ Fed Sao Paulo, Dept Biociencias, Sao Paulo - Brazil

^[5] Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 - USA

^[6] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 - USA

^[7] Fiocruz MS, Ctr Pesquisas Rene Rachou, Belo Horizonte, MG - Brazil

^[8] Univ Fed Santa Catarina, Dept Microbiol Imunol & Parasitol, Florianopolis, SC - Brazil

^[9] Univ Sao Paulo, Fac Med, Inst Coracao InCor, Sao Paulo - Brazil

^[10] Univ Santo Amaro, Sao Paulo - Brazil

^[11] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Imunol, Belo Horizonte, MG - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLOS PATHOGENS; v. 12, n. 4 APR 2016.
• Citações Web of Science: 5

Resumo

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. (AU)

• Processo FAPESP: 10/09361-8 - Estudo das bases celulares e moleculares do controle da imunodominância da resposta imune de linfócitos T CD8+ específicos induzidos pela infecção experimental por Trypanosoma cruzi ou imunização com adenovírus recombinantes
• Beneficiário: Jonatan Ersching
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 15/08814-2 - Papel de integrinas e receptores de quimiocinas na migração de células T CD8+ específicas geradas pela imunização genética com ASP-2 de Trypanosoma cruzi
• Beneficiário: Camila Pontes Ferreira
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 09/06820-4 - Caracterização das células apresentadoras de antígeno capazes de iniciar a reposta imune e controlar a imunodominância de Linfócitos T CD8+ específicos durante a infecção experimental pelo Trypanosoma cruzi
• Beneficiário: Maurício Martins Rodrigues
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/22514-3 - Estudo da migração de células T específicas geradas pela vacinação ou infecção pelo Trypanosoma cruzi
• Beneficiário: Jose Ronnie Carvalho de Vasconcelos
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores