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Infection and Immunity, October 2009, p. 4383-4395, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.01459-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Perforin and Gamma Interferon Expression Are Required for CD4+ and CD8+ T-Cell-Dependent Protective Immunity against a Human Parasite, Trypanosoma cruzi, Elicited by Heterologous Plasmid DNA Prime-Recombinant Adenovirus 5 Boost Vaccination{triangledown}

Bruna C. G. de Alencar,1,2 Pedro M. Persechini,3 Filipe A. Haolla,1,2 Gabriel de Oliveira,4 Jaline C. Silverio,4 Joseli Lannes-Vieira,4 Alexandre V. Machado,5 Ricardo T. Gazzinelli,5,6,7 Oscar Bruna-Romero,8 and Mauricio M. Rodrigues1,2*

Centro Interdisciplinar de Terapia Gênica (CINTERGEN),1 Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo-Escola Paulista de Medicina, Rua Mirassol 207, São Paulo, SP 04044-010, Brazil,2 Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Bloco G, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, RJ 21941-900, Brazil,3 Lab. Biologia Celular e Biologia das Interações, Instituto Oswaldo Cruz, FIOCRUZ, Av. Brasil no. 4365, Rio de Janeiro, RJ 21045-900, Brazil,4 Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil,5 Centro de Pesquisas René Rachou, FIOCRUZ, Av. Augusto de Lima 1715, Barro Preto, Belo Horizonte, Minas Gerais 30190-002, Brazil,6 Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605,7 Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antonio Carlos 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil8

Received 30 November 2008/ Returned for modification 13 January 2009/ Accepted 14 July 2009

A heterologous prime-boost strategy using plasmid DNA, followed by replication-defective recombinant adenovirus 5, is being proposed as a powerful way to elicit CD4+ and CD8+ T-cell-mediated protective immunity against intracellular pathogens. We confirmed this concept and furthered existing research by providing evidence that the heterologous prime-boost regimen using the gene encoding amastigote surface protein 2 elicited CD4+ and CD8+ T-cell-mediated protective immunity (reduction of acute parasitemia and prolonged survival) against experimental infection with Trypanosoma cruzi. Protective immunity correlated with the presence of in vivo antigen-specific cytotoxic activity prior to challenge. Based on this, our second goal was to determine the outcome of infection after heterologous prime-boost immunization of perforin-deficient mice. These mice were highly susceptible to infection. A detailed analysis of the cell-mediated immune responses in immunized perforin-deficient mice showed an impaired gamma interferon (IFN-{gamma}) secretion by immune spleen cells upon restimulation in vitro with soluble recombinant antigen. In spite of a normal numeric expansion, specific CD8+ T cells presented several functional defects detected in vivo (cytotoxicity) and in vitro (simultaneous expression of CD107a/IFN-{gamma} or IFN-{gamma}/tumor necrosis factor alpha) paralleled by a decreased expression of CD44 and KLRG-1. Our final goal was to determine the importance of IFN-{gamma} in the presence of highly cytotoxic T cells. Vaccinated IFN-{gamma}-deficient mice developed highly cytotoxic cells but failed to develop any protective immunity. Our study thus demonstrated a role for perforin and IFN-{gamma} in a number of T-cell-mediated effector functions and in the antiparasitic immunity generated by a heterologous plasmid DNA prime-adenovirus boost vaccination strategy.

* Corresponding author. Mailing address: CINTERGEN-UNIFESP-Escola Paulista de Medicina, Rua Mirassol 207, São Paulo, SP 04044-010, Brazil. Phone and fax: (55) (11) 5571-1095. E-mail: mrodrigues{at}unifesp.br

{triangledown} Published ahead of print on 3 August 2009.

Editor: J. F. Urban, Jr.

Infection and Immunity, October 2009, p. 4383-4395, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.01459-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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