Blockade of PD-1 Signaling Enhances Th2 Cell Responses and Aggravates Liver Immunopathology in Mice with Schistosomiasis japonica

Abstract

Background

More than 220 million people worldwide are chronically infected with schistosomes, causing severe disease or even death. The major pathological damage occurring in schistosomiasis is attributable to the granulomatous inflammatory response and liver fibrosis induced by schistosome eggs. The inflammatory response is tightly controlled and parallels immunosuppressive regulation, constantly maintaining immune homeostasis and limiting excessive immunopathologic damage in important host organs. It is well known that the activation of programmed death 1 (PD-1) signaling causes a significant suppression of T cell function. However, the roles of PD-1 signaling in modulating CD4 ⁺ T cell responses and immunopathology during schistosome infection, have yet to be defined.

Methodology/Principal Findings

Here, we show that PD-1 is upregulated in CD4 ⁺ T cells in Schistosoma japonicum ( S. japonicum)-infected patients. We also show the upregulation of PD-1 expression in CD4 ⁺ T cells in the spleens, mesenteric lymph nodes, and livers of mice with S. japonicum infection. Finally, we found that the blockade of PD-1 signaling enhanced CD4 ⁺ T helper 2 (Th2) cell responses and led to more severe liver immunopathology in mice with S. japonicum infection, without a reduction of egg production or deposition in the host liver.

Conclusions/Significance

Overall, our study suggests that PD-1 signaling is specifically induced to control Th2-associated inflammatory responses during schistosome infection and is beneficial to the development of PD-1-based control of liver immunopathology.

Author Summary

Schistosomiasis is a parasitic disease that affects approximately 220 million people and causes serious morbidity and economic problems mainly in (sub)tropical regions. After Schistosoma japonicum or Schistosoma mansoni infection, parasite eggs are trapped in host liver and induce liver inflammation and fibrosis, leading to irreversible impairment of the liver, and even death of the host. Meanwhile, schistosomes also induce strong regulatory mechanisms to suppress inflammation and prevent excessive immunopathology. Considering it is well known that PD-1 plays a critical role in suppressing T cell function, understanding the role of PD-1 in modulating immune responses during schistosome infection is necessary for the development of PD-1-based control of liver damage in schistosomiasis. Here, increased PD-1 expression in CD4 ⁺ T cells from both humans and mice with schistosome infection was shown. We further showed that PD-1 blockade preferentially augmented Th2 cell responses and ultimately resulted in more severe liver immunopathology in mice with Schistosomiasis japonica, suggesting that PD-1 signaling is beneficial to further explore therapeutic possibilities for preventing the excessive liver immunopathology.