Adenovirus Vector-Induced CD8(+) T Effector Memory Cell Differentiation and Recirculation, But Not Proliferation, Are Important for Protective Immunity Against Experimental Trypanosoma cruzi Infection

Adenovirus Vector-Induced CD8(+) T Effector Memory Cell Differentiation and Recirculation, But Not Proliferation, Are Important for Protective Immunity Against Experimental Trypanosoma cruzi Infection

Author Vasconcelos, Jose Ronnie Carvalho de Autor UNIFESP Google Scholar
Dominguez, Mariana Ribeiro Autor UNIFESP Google Scholar
Neves, Ramon Lemos Autor UNIFESP Google Scholar
Ersching, Jonatan Autor UNIFESP Google Scholar
Araujo, Adriano Autor UNIFESP Google Scholar
Santos, Luara I. Google Scholar
Virgilio, Fernando dos Santos Autor UNIFESP Google Scholar
Machado, Alexandre V. Google Scholar
Bruna-Romero, Oscar Google Scholar
Gazzinelli, Ricardo T. Google Scholar
Rodrigues, Mauricio Martins Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Universidade Federal de Minas Gerais (UFMG)
Fiocruz MS
Universidade Federal de Santa Catarina (UFSC)
Univ Massachusetts
Abstract Heterologous prime-boost vaccination using plasmid DNA followed by replication-defective adenovirus vector generates a large number of specific CD8(+) T effector memory (TEM) cells that provide long-term immunity against a variety of pathogens. in the present study, we initially characterized the frequency, phenotype, and function of these T cells in vaccinated mice that were subjected to infectious challenge with the human protozoan parasite Trypanosoma cruzi. We observed that the frequency of the specific CD8(+) T cells in the spleens of the vaccinated mice increased after challenge. Specific TEM cells differentiated into cells with a KLRG1(High) CD27(Low) CD43(Low) CD183(Low)T-bet(High)Eomes(Low) phenotype and capable to produce simultaneously the antiparasitic mediators IFN and TNF. Using the gzmBCreERT2/ROSA26EYFP transgenic mouse line, in which the cells that express Granzyme B after immunization, are indelibly labeled with enhanced yellow fluorescent protein, we confirmed that CD8(+) T cells present after challenge were indeed TEM cells that had been induced by vaccination. Subsequently, we observed that the in vivo increase in the frequency of the specific CD8(+) T cells was not because of an anamnestic immune response. Most importantly, after challenge, the increase in the frequency of specific cells and the protective immunity they mediate were insensitive to treatment with the cytostatic toxic agent hydroxyurea. We have previously described that the administration of the drug FTY720, which reduces lymphocyte recirculation, severely impairs protective immunity, and our evidence supports the model that when large amounts of antigen-experienced CD8(+) TEM cells are present after heterologous prime-boost vaccination, differentiation, and recirculation, rather than proliferation, are key for the resultant protective immunity.
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Grant number FAPESP: 2009/06820-4
FAPESP: 2013/13668/0
FAPESP: 2012/22514-3
Date 2014-04-01
Published in Human Gene Therapy. New Rochelle: Mary Ann Liebert, Inc, v. 25, n. 4, p. 350-363, 2014.
ISSN 1043-0342 (Sherpa/Romeo, impact factor)
Publisher Mary Ann Liebert, Inc
Extent 350-363
Origin http://dx.doi.org/10.1089/hum.2013.218
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000334915500010
URI http://repositorio.unifesp.br/handle/11600/37572

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