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(s):Show less -

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]}

Affiliation:Show less -

^[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

• Document type: Journal article
• Source: PLOS PATHOGENS; v. 12, n. 4 APR 2016.
• Web of Science Citations: 5

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. (AU)

• FAPESP's process: 10/09361-8 - Study of molecular and cellular basis of the control of specific T CD8+ lymphocyte immunodominant immune response during experimental infection with Trypanosoma cruzi or recombinant adenoviruses immunization
• Grantee: Jonatan Ersching
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 15/08814-2 - Role of integrin receptors and chemokines in the migration of specific CD8+ T cells generated by genetic immunization with ASP -2 Trypanosoma cruzi
• Grantee: Camila Pontes Ferreira
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 09/06820-4 - Characterization of antigen presenting cells capable of initiating the immune response and control the immunodominance during Trypanosoma cruzi infection
• Grantee: Maurício Martins Rodrigues
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/22514-3 - Migration study of specific T cells generated by vaccination or Trypanosoma cruzi infection
• Grantee: Jose Ronnie Carvalho de Vasconcelos
• Support Opportunities: Research Grants - Young Investigators Grants