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Role of receptor CXCR3, CCR2 and CCR5 in cell migration in specific CD8+ t cells after genetic immunization with the ASP-2 Trypanosoma Cruzi

Grant number: 13/15794-2
Support type:Scholarships in Brazil - Master
Effective date (Start): October 01, 2013
Effective date (End): August 31, 2015
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Jose Ronnie Carvalho de Vasconcelos
Grantee:Camila Pontes Ferreira
Home Institution: Centro de Terapia Celular e Molecular. Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated research grant:12/22514-3 - Migration study of specific T cells generated by vaccination or Trypanosoma cruzi infection, AP.JP

Abstract

CD8+ T cells play a key role in protective immunity against intracellular pathogens such as Trypanosoma cruzi, the causative agent of Chagas' disease. The presence of these effector cells at the sites where pathogens multiply is only possible due to the recirculation after activationin secondary lymphoid organs. The integrin adhesion molecules and chemokine receptors may play a critical role in this process allowing these cells to migrate to non-peripheral lymphoid tissues. Recently, we observed that treatment with FTY720 drug led the retention of specific CD8+ T cells in the lymph node of C57BL/6 mice infected making them susceptible to infection. The highly A/Sn mice vaccinated also become susceptible to infection. This result was the first experimental evidence that the recirculation of lymphocytes is important for affecting the immune response against T. cruzi. Furthermore, chemokine receptor type 1, for example, CXCR3 and CCR5, and type 2 CCR2/CCL2 play an important role in the migration of leukocytes to the site of infection, and in case of CXCR3, affects the generation of T cells memory in models of viral infection. In view of this, the overall goal of this project is to study the role of chemokine receptors CCR5 and CXCR3 in the migration of specific CD8+ T cells and CCR2/CCL2 (MCP-1) after genetic immunization based on heterologous prime-boost with Plasmid and Adenovirus containing the gene expressing the protein surface amastigote 2 (ASP-2) T. cruzi. To do that, we will treat groups of A/Sn mice previously immunized with these specific antibodies for some molecules. After this treatment, we will analyze the specific immune response and protective immunity after experimental infection with T. cruzi. Groups of deficient mice for some of these molecules will also be immunized and infected. We expect that those animals treated with these antibodies or the immune deficient mice will generate immune response in the lymphoid organs and liver, but they may become susceptible to experimental infection due to blocking the ability of T effector lymphocytes migrate to the sites where pathogens multiply. If this does in fact occur, we demonstrate the importance of the migration of T lymphocytes, and the molecules that mediate this process in the immunity induced by experimental heterologous prime-boost vaccination regimen.