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

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 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.

Host‐parasite dynamics in Chagas disease from systemic to hyper‐local scales

“…To keep up with the parasite, effector cells must be continually deployed to infection foci in many organs. There appears to be no problem with T‐cell homing and entry into infected tissues, 203 which is dependent on expression of integrins including VLA‐4 and LFA‐1, 174,204 and CXCR3 chemokine receptor signalling 205 . After extravasation though, the distinct microenvironment of each organ potentially drives phenotypic changes to infiltrating cells, and in some cases, the effect may be tolerogenic and incompatible with local sterilization.…”

CXCR3 chemokine receptor contributes to specific CD8+ T cell activation by pDC during infection with intracellular pathogens

“…During infection with parainfluenza, CXCR3 guides CD4 + T cells to the lungs [12]. Also, we demonstrated that CXCR3 is essential to specific CD8 + T cell migration into infected hearts and infection control during immunization with ASP-2-based anti-T. cruzi vaccine [13].…”

“…CXCR3 chemokine receptor is highly expressed on T lymphocytes surface during Th1 responses against intracellular infection, such as with Trypanosoma cruzi. Previously, our group demonstrated that CXCR3 chemokine receptor was important to protect A/Sn vaccinated mice against death after T. cruzi infection [13]. Here, we aimed to examine whether CXCR3 chemokine contributes to specific CD8 + T cells migration, activation, and functionality.…”

“…Previously, our group described that CXCR3 is critical for migration of specific CD8 + T cells into the heart during vaccination with ASP-2 and infection with T. cruzi [13]. Firstly, we analyzed the presence of CD8 + T cells in the heart using confocal microscopy, and differently Anti-CXCR3 group decreased number of specific CD8 + T cells as well as polyfunctionality after infection with T. cruzi.…”

Incomplete recruitment of protective T cells facilitatesTrypanosoma cruzipersistence in the mouse colon

“…T cell recruitment during T. cruzi infection is driven by secretion of chemokines from infected cells. For example, the CXCR3 ligands CXCL9 and CXCL10 have been implicated in cardiac infiltration (32). IFN-γ and TNF-α expression by antigen specific CD8 + T cells (4), and subsequent iNOS expression (33–35), potentially from recruited innate monocytes or from somatic cells of the infected tissue, then increases the local concentration of reactive nitrogen species.…”