title: Regulation of Trypanosoma cruzi-induced myocarditis by programmed death cell receptor 1.
abstract: Trypanosoma cruzi infection 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. cruzi modulates 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 during T. cruzi-induced acute myocarditis in mice. Cytometry assays showed that PD-1 and its ligands are strongly upregulated in lymphocytes and APC in response to T. cruzi infection in vivo and in 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 by T. cruzi and provide additional insight into the regulatory mechanisms in the pathogenesis of Chagas' disease.
authors.affiliation: Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, USP Av. Bandeirantes, 3900 Ribeirão Preto, São Paulo 14049-900, Brazil.
authors.forename: Fredy R S
authors.initials: FR
authors.lastname: Gutierrez
authors.forename: Flávia S
authors.initials: FS
authors.lastname: Mariano
authors.forename: Carlo J F
authors.initials: CJ
authors.lastname: Oliveira
authors.forename: Wander R
authors.initials: WR
authors.lastname: Pavanelli
authors.forename: Paulo M M
authors.initials: PM
authors.lastname: Guedes
authors.forename: Grace K
authors.initials: GK
authors.lastname: Silva
authors.forename: Ana P
authors.initials: AP
authors.lastname: Campanelli
authors.forename: Cristiane M
authors.initials: CM
authors.lastname: Milanezi
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Tasuku
authors.initials: T
authors.lastname: Honjo
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.forename: Julio C S
authors.initials: JC
authors.lastname: Aliberti
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000276:immunology* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D002598:Chagas Cardiomyopathy / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014349:Trypanosoma cruzi / Q000276:immunology*
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor