Regulation of Trypanosoma cruzi-Induced Myocarditis by Programmed Death Cell Receptor 1

• DOI: 10.1128/iai.01047-10
• Publication Date: 2011-03-01T21:45:09Z
• Authors: Fredy R. S. Gutie...; Flávia S. Mariano; Carlo J. F. Oliveira; Wander R. Pavanelli; Paulo M. M. Guedes; Grace K. Silva; Ana P. Campanelli; Cristiane M. Mila...; Miyuki Azuma; Tasuku Honjo; Mauro M. Teixeira; Julio C. S. Aliberti; João S. Silva
• Keywords: Chagas Cardiomyopathy; Mice, Knockout; 0301 basic medicine; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes; Trypanosoma cruzi; Programmed Cell Death 1 Receptor; Fluorescent Antibody Technique; Enzyme-Linked Immunosorbent Assay; Cell Separation; Flow Cytometry; Immunohistochemistry; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Antigens, Surface; Animals; Apoptosis Regulatory Proteins; Signal Transduction

ABSTRACTTrypanosoma cruziinfection causes intense myocarditis, leading to cardiomyopathy and severe cardiac dysfunction. Protective adaptive immunity depends on balanced signaling through a T cell receptor and coreceptors expressed on the T cell surface. Such coreceptors can trigger stimulatory or inhibitory signals after binding to their ligands in antigen-presenting cells (APC).T. cruzimodulates the expression of coreceptors in lymphocytes after infection. Deregulated inflammation may be due to unbalanced expression of these molecules. Programmed death cell receptor 1 (PD-1) is a negative T cell coreceptor that has been associated with T cell anergy or exhaustion and persistent intracellular infections. We aimed to study the role of PD-1 duringT. cruzi-induced acute myocarditis in mice. Cytometry assays showed that PD-1 and its ligands are strongly upregulated in lymphocytes and APC in response toT. cruziinfectionin vivoandin vitro. Lymphocytes infiltrating the myocardium exhibited high levels of expression of these molecules. An increased cardiac inflammatory response was found in mice treated with blocking antibodies against PD-1, PD-L1, and to a lesser extent, PD-L2, compared to that found in mice treated with rat IgG. Similar results in PD-1−/−mice were obtained. Moreover, the PD-1 blockade/deficiency led to reduced parasitemia and tissue parasitism but increased mortality. These results suggest the participation of a PD-1 signaling pathway in the control of acute myocarditis induced byT. cruziand provide additional insight into the regulatory mechanisms in the pathogenesis of Chagas' disease.