CXCR3 Chemokine Receptor Guides Trypanosoma Cruzi-Specific T-Cells Triggered by DNA/Adenovirus ASP2 Vaccine to Heart Tissue After Challenge
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University of Massachusetts Medical School eScholarship@UMMS Open Access Articles Open Access Publications by UMMS Authors 2019-07-29 CXCR3 chemokine receptor guides Trypanosoma cruzi-specific -T cells triggered by DNA/adenovirus ASP2 vaccine to heart tissue after challenge Camila Pontes Ferreira Federal University of São Paulo Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/oapubs Part of the Hemic and Immune Systems Commons, Parasitic Diseases Commons, Parasitology Commons, and the Pathology Commons Repository Citation Pontes Ferreira C, Cariste LM, Ferri Moraschi B, Ferrarini Zanetti B, Won Han S, Araki Ribeiro D, Vieira Machado A, Lannes-Vieira J, Gazzinelli RT, Vasconcelos JR. (2019). CXCR3 chemokine receptor guides Trypanosoma cruzi-specific -cellsT triggered by DNA/adenovirus ASP2 vaccine to heart tissue after challenge. Open Access Articles. https://doi.org/10.1371/journal.pntd.0007597. 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RESEARCH ARTICLE CXCR3 chemokine receptor guides Trypanosoma cruzi-specific T-cells triggered by DNA/adenovirus ASP2 vaccine to heart tissue after challenge Camila Pontes Ferreira1, Leonardo Moro Cariste2, Barbara Ferri Moraschi1, Bianca Ferrarini Zanetti3, Sang Won Han3, Daniel Araki Ribeiro2, Alexandre Vieira Machado4, Joseli Lannes-Vieira5, Ricardo Tostes Gazzinelli4,6, Jose Ronnie 1,2 a1111111111 Carvalho VasconcelosID * a1111111111 a1111111111 1 Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, São Paulo, Brazil, 2 Department of Biosciences, Federal University of São Paulo, Santos, Brazil, 3 Department of a1111111111 Biophysics, Federal University of São Paulo, São Paulo, Brazil, 4 Rene Rachou Research Center, Fiocruz, a1111111111 Minas Gerais, Brazil, 5 Laboratory of Biology of the Interactions, Oswaldo Cruz Institute/Fiocruz, Rio de Janeiro, Brazil, 6 Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, United States ofAmerica * [email protected] OPEN ACCESS Citation: Pontes Ferreira C, Cariste LM, Ferri Moraschi B, Ferrarini Zanetti B, Won Han S, Araki Abstract Ribeiro D, et al. (2019) CXCR3 chemokine receptor + guides Trypanosoma cruzi-specific T-cells CD8 T lymphocytes play an important role in controlling infections by intracellular patho- + triggered by DNA/adenovirus ASP2 vaccine to gens. Chemokines and their receptors are crucial for the migration of CD8 T-lymphocytes, heart tissue after challenge. PLoS Negl Trop Dis 13 which are the main IFNγ producers and cytotoxic effectors cells. Although the participation (7): e0007597. https://doi.org/10.1371/journal. of chemokine ligands and receptors has been largely explored in viral infection, much less is pntd.0007597 known in infection by Trypanosoma cruzi, the causative agent of Chagas disease. After T. Editor: Juan M. Bustamante, University of Georgia, cruzi infection, CXCR3 chemokine receptor is highly expressed on the surface of CD8+ T- UNITED STATES lymphocytes. Here, we hypothesized that CXCR3 is a key molecule for migration of para- Received: March 14, 2019 site-specific CD8+ T-cells towards infected tissues, where they may play their effector activi- Accepted: July 2, 2019 ties. Using a model of induction of resistance to highly susceptible A/Sn mice using an Published: July 29, 2019 ASP2-carrying DNA/adenovirus prime-boost strategy, we showed that CXCR3 expression + Copyright: © 2019 Pontes Ferreira et al. This is an was upregulated on CD8 T-cells, which selectively migrated towards its ligands CXCL9 open access article distributed under the terms of and CXCL10. Anti-CXCR3 administration reversed the vaccine-induced resistance to T. the Creative Commons Attribution License, which cruzi infection in a way associated with hampered cytotoxic activity and increased proapop- permits unrestricted use, distribution, and totic markers on the H2KK-restricted TEWETGQI-specific CD8+ T-cells. Furthermore, reproduction in any medium, provided the original + author and source are credited. 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 Data Availability Statement: All relevant data are + within the manuscript and its Supporting ligands as key molecules to drive T. cruzi-specific effector CD8 T-cells into the infected Information files. heart tissue. The unveiling of the process driving cell migration and colonization of infected Funding: This work was supported by grant from tissues by pathogen-specific effector T-cells is a crucial requirement to the development of FundacËão de Amparo à Pesquisa do Estado de São vaccine strategies. Paulo (http://www.fapesp.br/) (JRCV: 2012/22514- 3; 2018/15607-1 CF: 2015/08814-2; LC: 2017/ 11499-7; BM: 2016/02840-4), Instituto Nacional de Ciência e Tecnologia em Vacinas (http://inct.cnpq. PLOS Neglected Tropical Diseases | https://doi.org/10.1371/journal.pntd.0007597 July 29, 2019 1 / 27 CXCR3 chemokine receptor impacts in specific CD8+ T cell migration to the heart tissue br/), CoordenacËão de AperfeicËoamento de Pessoal de NõÂvel Superior (http://www.capes.gov.br/) and Author summary Conselho Nacional de Desenvolvimento CientõÂfico e TecnoloÂgico (http://cnpq.br/). RTG: Fapemig and Chemokine receptors and cell adhesion molecules are essential for T lymphocytes migra- National Institutes of Health (1R01AI116577). The tion into infected tissues. Previously, our group demonstrated that CXCR3 receptor was funders had no role in study design, data collection highly expressed on specific CD8+ T-cells surface after immunization and infection by T. and analysis, decision to publish, or preparation of cruzi. Also, recirculation of specific CD8+ T-cells was more important than proliferation the manuscript. to control the infection by T cruzi. As CD8+ T lymphocytes are responsible for controlling Competing interests: The authors declare that the T. cruzi infection by releasing IFN-γ or by direct cytotoxicity against infected target cells, research was conducted in the absence of any our aim was to analyze the role of the chemokine receptor CXCR3 in the migration of spe- commercial or financial relationships that could be cific CD8+ T-cells towards infected tissues. Our results revealed that intervention on construed as a potential conflict of interest. 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 cru- cial for drive the pathogen-specific effector to sites of infection and, therefore, to clarify this requirement is a crucial strategy for vaccine development. Introduction The causative agent of Chagas disease Trypanosoma cruzi is an intracellular parasite that infects a variety of cells of the mammalian host [1,2]. The activation of adaptive immune response occurs by recruiting T lymphocytes to the infection sites after the presentation of try- pomastigote/amastigote-related proteins via MHC-I or MHC-II [3,4]. CD8+ T lymphocytes are the cells primarily responsible for controlling intracellular pathogens such as T. cruzi [5± 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 multiple antiparasitic mechanisms mediated by these cells include secretion of cytokines and direct cytotoxicity against infected cells [9,10]. 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]. Our group has been studying the prime-boost protocol that uses plasmid vector for prim- ing and a replication-defective human adenovirus type 5 (AdHu5 vector) [9,12] for boosting, both containing an insertion of the amastigote surface protein 2 (ASP2) gene ASP2. 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]. Recently, we have shown that more than proliferative response, the specific CD8+ T-cells need to recirculate to exert protec- tion against infection in A/Sn mice [9,13]. Chemokine molecules are small chemotactic molecules responsible for the guidance of leu- kocyte migration during homeostasis and inflammation [15]. In addition to cell migration, chemokines acting as costimulatory molecules involved in T-lymphocytes activation, differen- tiation and proliferation [16,17]. Pro-inflammatory chemokines are induced by infection with different pathogens and molecular inflammatory stimuli [18]. Chemokines expression are induced by an IFN-γ- and TNF-enriched Th1-type immune response triggered by infection with intracellular pathogens [19,20] such as T. cruzi [21±23]. Naive T cells differentiate into cytokine-producing cells such as IFN-γ, IL-2 and TNF; this differentiation