title: PD-L2 negatively regulates Th1-mediated immunopathology during Fasciola hepatica infection.
abstract: Macrophage plasticity is critical for controlling inflammation including those produced by helminth infections, where alternatively activated macrophages (AAM) are accumulated in tissues. AAM expressing the co-inhibitory molecule programmed death ligand 2 (PD-L2), which is capable of binding programmed death 1 (PD-1) expressed on activated T cells, have been demonstrated in different parasitic infections. However, the role of PD-L2 during F. hepatica infection has not yet been explored. We observed that F. hepatica infection or a F. hepatica total extract (TE) injection increased the expression of PD-L2 on peritoneal macrophages. In addition, the absence of PD-L2 expression correlated with an increase in susceptibility to F. hepatica infection, as evidenced by the shorter survival and increased liver damage observed in PD-L2 deficient (KO) mice. We assessed the contribution of the PD-L2 pathway to Th2 polarization during this infection, and found that the absence of PD-L2 caused a diminished Th2 type cytokine production by TE stimulated splenocytes from PD-L2 KO infected compared with WT mice. Besides, splenocytes and intrahepatic leukocytes from infected PD-L2 KO mice showed higher levels of IFN-γ than those from WT mice. Arginase expression and activity and IL-10 production were reduced in macrophages from PD-L2 KO mice compared to those from WT mice, revealing a strong correlation between PD-L2 expression and AAM polarization. Taken together, our data indicate that PD-L2 expression in macrophages is critical for AAM induction and the maintenance of an optimal balance between the Th1- and Th2-type immune responses to assure host survival during F. hepatica infection.
authors: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Medina Allende y Haya de la Torre, Ciudad Universitaria, Córdoba, Argentina.
authors: Cinthia C
authors: CC
authors: Stempin
authors: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Medina Allende y Haya de la Torre, Ciudad Universitaria, Córdoba, Argentina.
authors: Claudia C
authors: CC
authors: Motrán
authors: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Medina Allende y Haya de la Torre, Ciudad Universitaria, Córdoba, Argentina.
authors: María P
authors: MP
authors: Aoki
authors: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Medina Allende y Haya de la Torre, Ciudad Universitaria, Córdoba, Argentina.
authors: Cristian R
authors: CR
authors: Falcón
authors: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Medina Allende y Haya de la Torre, Ciudad Universitaria, Córdoba, Argentina.
authors: Fabio M
authors: FM
authors: Cerbán
authors: Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Medina Allende y Haya de la Torre, Ciudad Universitaria, Córdoba, Argentina.
authors: Laura
authors: L
authors: Cervi
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D000066670:Cell Plasticity; D002478:Cells, Cultured; D005210:Fasciola hepatica / Q000276:immunology / Q000472:pathogenicity*; D005211:Fascioliasis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D055786:Gene Knockout Techniques; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000469:parasitology; D051379:Mice; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics* / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology*
chemical_list: C000611649:IFNG protein, mouse; C556062:IL10 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein; D016753:Interleukin-10; D007371:Interferon-gamma; D001119:Arginase
keywords: F. hepatica; PD-L2; Th1 response; infection; macrophage