Abstract
BackgroundMore 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 FindingsHere, 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/SignificanceOverall, 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.
Highlights
Schistosomiasis is an infectious disease that affects at least 220 million people worldwide and causes serious morbidity and economic problems in developing countries [1,2]
Our study suggests that programmed death 1 (PD-1) signaling is induced to control T helper 2 (Th2)-associated inflammatory responses during schistosome infection and is beneficial to the development of PD-1-based control of liver 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
Summary
Schistosomiasis is an infectious disease that affects at least 220 million people worldwide and causes serious morbidity and economic problems in developing countries [1,2]. During infection with Schistosoma japonicum (S. japonicum) or S. mansoni, granulomas form around eggs that are trapped in the host liver This long-term immune-mediated granulomatous response results in severe fibrosis in the liver and eventually causes extensive tissue scarring, leading to irreversible impairment of affected organs, the liver, and even death of the host [3,4,5]. The CD4+ T cell subsets play a critical role to develop hepatic granulomas and to maintain a balanced granulomatous response to prevent the growth of hepatic fibrosis during schistosomiasis [6,7]. Very little is known about the regulation of PD-1 in CD4+ T cells or the impact of its signaling on the development of CD4+ T cell responses and egg-induced immunopathology during schistosome infections. The roles of PD-1 signaling in modulating CD4+ T cell responses and immunopathology during schistosome infection, have yet to be defined
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