CXCR3 chemokine receptor guides Trypanosoma cruzi-specific T-cells triggered by DNA/adenovirus ASP2 vaccine to heart tissue after challenge

Author(s)

Ferreira, Camila Pontes ^[1] ; Cariste, Leonardo Moro ^[2] ; Moraschi, Barbara Ferri ^[1] ; Zanetti, Bianca Ferrarini ^[3] ; Han, Sang Won ^[2] ; Ribeiro, Daniel Araki ^[2] ; Machado, Alexandre Vieira ^[4] ; Lannes-Vieira, Joseli ^[5] ; Gazzinelli, Ricardo Tostes ^{[4, 6]} ; Carvalho Vasconcelos, Jose Ronnie ^{[1, 2]}

Affiliation

^[1] Univ Fed Sao Paulo, Dept Microbiol Immunol & Parasitol, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Dept Biosci, Santos - Brazil

^[3] Univ Fed Sao Paulo, Dept Biophys, Sao Paulo - Brazil

^[4] Fiocruz MS, Rene Rachou Res Ctr, Belo Horizonte, MG - Brazil

^[5] Fiocruz MS, Oswaldo Cruz Inst, Lab Biol Interact, Rio De Janeiro - Brazil

^[6] Univ Massachusetts, Med Sch, Div Infect Dis & Immunol, Worcester, MA - USA

• Document type: Journal article
• Source: PLoS Neglected Tropical Diseases; v. 13, n. 7 JUL 2019.
• Web of Science Citations: 0

Abstract

CD8(+) T lymphocytes play an important role in controlling infections by intracellular pathogens. Chemokines and their receptors are crucial for the migration of CD8(+) T-lymphocytes, which are the main IFN gamma producers and cytotoxic effectors cells. Although the participation of chemokine ligands and receptors has been largely explored in viral infection, much less is known in infection by Trypanosoma cruzi, the causative agent of Chagas disease. After T. cruzi infection, CXCR3 chemokine receptor is highly expressed on the surface of CD8(+) T-lymphocytes. Here, we hypothesized that CXCR3 is a key molecule for migration of parasite-specific CD8(+) T-cells towards infected tissues, where they may play their effector activities. Using a model of induction of resistance to highly susceptible A/Sn mice using an ASP2-carrying DNA/adenovirus prime-boost strategy, we showed that CXCR3 expression was upregulated on CD8(+) T-cells, which selectively migrated towards its ligands CXCL9 and CXCL10. Anti-CXCR3 administration reversed the vaccine-induced resistance to T. cruzi infection in a way associated with hampered cytotoxic activity and increased proapoptotic markers on the H2K(K)-restricted TEWETGQI-specific CD8(+) T-cells. Furthermore, CXCR3 receptor critically guided TEWETGQI-specific effector CD8(+) T-cells to the infected heart tissue that express CXCL9 and CXCL10. Overall, our study pointed CXCR3 and its ligands as key molecules to drive T. cruzi-specific effector CD8(+) T-cells into the infected heart tissue. The unveiling of the process driving cell migration and colonization of infected tissues by pathogen-specific effector T-cells is a crucial requirement to the development of vaccine strategies. Author summary Chemokine receptors and cell adhesion molecules are essential for T lymphocytes migration into infected tissues. Previously, our group demonstrated that CXCR3 receptor was highly expressed on specific CD8(+) T-cells surface after immunization and infection by T. cruzi. Also, recirculation of specific CD8(+) T-cells was more important than proliferation to control the infection by T cruzi. As CD8(+) T lymphocytes are responsible for controlling T. cruzi infection by releasing IFN-gamma or by direct cytotoxicity against infected target cells, our aim was to analyze the role of the chemokine receptor CXCR3 in the migration of specific CD8(+) T-cells towards infected tissues. Our results revealed that intervention on CXCR3 by administration of a blocking anti-CXCR3 antibody decreased CD8(+) T-cell migration, hampering the access of parasite-specific effector cell into the heart tissue of mice infected by T. cruzi. Therefore, to induce the appropriate migration footmarks is crucial for drive the pathogen-specific effector to sites of infection and, therefore, to clarify this requirement is a crucial strategy for vaccine development. (AU)

• FAPESP's process: 16/02840-4 - Role of pharmacological inhibitor mTOR rapamycin in response of memory CD8+ T cells induced by heterologous prime-boost immunization
• Grantee: Barbara Ferri Moraschi
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 17/11499-7 - Role of CX3CR1 chemokine receptor and the integrin LFA-1 in the differentiation and activation of CD8 + t lymphocytes during Trypanosoma cruzi infection
• Grantee: Leonardo Moro Cariste
• Support Opportunities: Scholarships in Brazil - Master
• 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
• FAPESP's process: 18/15607-1 - Role of specific CD4+ and CD8+ T cells generated by different vaccination protocols against experimental Trypanosoma cruzi infection
• Grantee: Jose Ronnie Carvalho de Vasconcelos
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• 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)