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 IFNγ 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 H2KK-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.
Highlights
The causative agent of Chagas disease Trypanosoma cruzi is an intracellular parasite that infects a variety of cells of the mammalian host [1,2]
As CD8+ T lymphocytes are responsible for controlling T. cruzi infection by releasing IFN-γ 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
Summary
The causative agent of Chagas disease Trypanosoma cruzi is an intracellular parasite that infects a variety of cells of the mammalian host [1,2]. CD8+ T lymphocytes are the cells primarily responsible for controlling intracellular pathogens such as T. cruzi [5,6,7]. Their relevance to the control of T. cruzi infection was demonstrated during the infection of CD8-deficient mice, or by the blockade of this molecule using monoclonal antibodies; in both cases, animals did not survive to infection [8]. The importance of the immune response mediated by CD8+ T lymphocytes, which promote resistance to T. cruzi infection, has led several groups to investigate different vaccine strategies [11]. That immunization protocol can induce a strong CD8-mediated response able to protect the highly susceptible A/Sn mice to experimental T. cruzi infection [13,14]. We have shown that more than proliferative response, the specific CD8+ T-cells need to recirculate to exert protection against infection in A/Sn mice [9,13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
