title: Pathogen-induced proapoptotic phenotype and high CD95 (Fas) expression accompany a suboptimal CD8+ T-cell response: reversal by adenoviral vaccine.
abstract: MHC class Ia-restricted CD8(+) T cells are important mediators of the adaptive immune response against infections caused by intracellular microorganisms. Whereas antigen-specific effector CD8(+) T cells can clear infection caused by intracellular pathogens, in some circumstances, the immune response is suboptimal and the microorganisms survive, causing host death or chronic infection. Here, we explored the cellular and molecular mechanisms that could explain why CD8(+) T cell-mediated immunity during infection with the human protozoan parasite Trypanosoma cruzi is not optimal. For that purpose, we compared the CD8(+) T-cell mediated immune responses in mice infected with T. cruzi or vaccinated with a recombinant adenovirus expressing an immunodominant parasite antigen. Several functional and phenotypic characteristics of specific CD8(+) T cells overlapped. Among few exceptions was an accelerated expansion of the immune response in adenoviral vaccinated mice when compared to infected ones. Also, there was an upregulated expression of the apoptotic-signaling receptor CD95 on the surface of specific T cells from infected mice, which was not observed in the case of adenoviral-vaccinated mice. Most importantly, adenoviral vaccine provided at the time of infection significantly reduced the upregulation of CD95 expression and the proapoptotic phenotype of pathogen-specific CD8(+) cells expanded during infection. In parallel, infected adenovirus-vaccinated mice had a stronger CD8 T-cell mediated immune response and survived an otherwise lethal infection. We concluded that a suboptimal CD8(+) T-cell response is associated with an upregulation of CD95 expression and a proapoptotic phenotype. Both can be blocked by adenoviral vaccination.
authors.affiliation: Centro de Terapia Celular e Molecular (CTCMol), Universidade Federal de São Paulo-Escola Paulista de Medicina, São Paulo, São Paulo, Brazil.
authors.forename: José Ronnie
authors.initials: JR
authors.lastname: Vasconcelos
authors.forename: Oscar
authors.initials: O
authors.lastname: Bruña-Romero
authors.forename: Adriano F
authors.initials: AF
authors.lastname: Araújo
authors.forename: Mariana R
authors.initials: MR
authors.lastname: Dominguez
authors.forename: Jonatan
authors.initials: J
authors.lastname: Ersching
authors.forename: Bruna C G
authors.initials: BC
authors.lastname: de Alencar
authors.forename: Alexandre V
authors.initials: AV
authors.lastname: Machado
authors.forename: Ricardo T
authors.initials: RT
authors.lastname: Gazzinelli
authors.forename: Karina R
authors.initials: KR
authors.lastname: Bortoluci
authors.forename: Gustavo P
authors.initials: GP
authors.lastname: Amarante-Mendes
authors.forename: Marcela F
authors.initials: MF
authors.lastname: Lopes
authors.forename: Mauricio M
authors.initials: MM
authors.lastname: Rodrigues
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis / Q000276:immunology; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D014355:Chagas Disease / Q000276:immunology / Q000517:prevention & control; D007371:Interferon-gamma / Q000096:biosynthesis; D052118:Lysosomal-Associated Membrane Protein 1 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009439:Neuraminidase / Q000276:immunology*; D016052:Protozoan Vaccines / Q000276:immunology*; D014349:Trypanosoma cruzi / Q000276:immunology* / Q000472:pathogenicity; D014614:Vaccines, Synthetic / Q000276:immunology; D019014:fas Receptor / Q000096:biosynthesis*
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D052118:Lysosomal-Associated Membrane Protein 1; D016052:Protozoan Vaccines; D014614:Vaccines, Synthetic; D019014:fas Receptor; D007371:Interferon-gamma; C493236:ASP-2 protein, Trypanosoma cruzi; D009439:Neuraminidase