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

Abstract

Macrophage plasticity is critical for controlling inflammation including thoseproduced by helminth infections, where alternatively activated macrophages (AAM)are accumulated in tissues. AAM expressing the co-inhibitory molecule programmeddeath ligand 2 (PD-L2), which is capable of binding programmed death 1 (PD-1) expressed on activated T cells, have been demonstrated in different parasiticinfections. However, the role of PD-L2 during F. hepatica infection has not yet beenexplored. 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 damageobserved in PD-L2 deficient (KO) mice. We assessed the contribution of the PD-L2pathway to Th2 polarization during this infection, and found that the absence of PD-L2caused a diminished Th2 type cytokine production by TE stimulated splenocytes fromPD-L2 KO infected compared with WT mice. Besides, splenocytes and intrahepaticleukocytes from infected PD-L2 KO mice showed higher levels of IFN-γ than thosefrom WT mice. Arginase expression and activity and IL-10 production were reducedin macrophages from PD-L2 KO mice compared to those from WT mice, revealing astrong correlation between PD-L2 expression and AAM polarization. Taken together,our data indicate that PD-L2 expression in macrophages is critical for AAM inductionand the maintenance of an optimal balance between the Th1- and Th2-type immuneresponses to assure host survival during F. hepatica infection.