Oncotarget

Research Papers:

PD-L2 negatively regulates Th1-mediated immunopathology during Fasciola hepatica infection

Cinthia C. Stempin, Claudia C. Motrán, María P. Aoki, Cristian R. Falcón, Fabio M. Cerbán and Laura Cervi _

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Oncotarget. 2016; 7:77721-77731. https://doi.org/10.18632/oncotarget.12790

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Abstract

Cinthia C. Stempin1, Claudia C. Motrán1, María P. Aoki1, Cristian R. Falcón1, Fabio M. Cerbán1,*, Laura Cervi1,*

1Centro 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

*These authors have contributed equally to this work

Correspondence to:

Laura Cervi, email: [email protected]

Keywords: macrophage, PD-L2, F. hepatica, Th1 response, infection

Received: December 06, 2015    Accepted: October 01, 2016    Published: October 21, 2016

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.


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