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

CINTHIA STEMPIN; CRISTINA MOTRAN; AOKI, MP; CRISTIAN FALCÓN; CERBAN F; LAURA CERVI

Oncotarget

Impact Journals

Año: 2016 vol. 7 p. 77721 - 77731

Macrophage plasticity is critical for controlling inflammation during infections, such asthose produced by helminths where alternatively activated macrophages (AAM) areaccumulated in tissues. Furthermore, in different helminth infections has beendemonstrated, an increased expression of the co-inhibitory molecule programmed deathligand 2 (PD-L2) on AAM, capable of binding programmed death 1 (PD-1), which isexpressed on activated T cells. However, the role of PD-L2 during F. hepatica infectionhas not yet been explored. We observed that F. hepatica infection or F. hepatica totalextract (TE) injection up-regulated the expression of PD-L2 on peritoneal macrophages. Inaddition, the absence of PD-L2 expression correlated with an increase in susceptibility to F.hepatica infection as evidenced by a shorter survival and increased liver damage in PD-L2deficient (KO) mice. Concomitantly, a decrease in the production of the Th2 cytokines IL-4and IL-10, and an increased production of IFN-γ were observed in splenocytes andintrahepatic leucocytes from PD-L2 KO compared with WT mice. Moreover, after 24 h ofintraperitoneal TE injection, arginase I expression and activity was significantly upregulatedin peritoneal cells (PC) from WT but not from PD-L2 KO mice, with PC from 24h F. hepatica-infected PD-L2 KO mice showing lower arginase I activity compared to PCfrom WT mice. These results indicate that PD-L2 expression in macrophages is critical forAAM induction during F. hepatica infection and it is important for maintaining an optimalbalance between the Th1- and Th2-type immune responses to assure host survival duringthis infection.