Abstract
Following Schistosoma japonicum (S. japonicum) infection, granulomatous responses are induced by parasite eggs trapped in host organs, particular in the liver, during the acute stage of disease. While excessive liver granulomatous responses can lead to more severe fibrosis and circulatory impairment in chronically infected host. However, the exact mechanism of hepatic granuloma formation has remained obscure. In this study, we for the first time showed that follicular helper T (Tfh) cells are recruited to the liver to upregulate hepatic granuloma formation and liver injury in S. japonicum-infected mice, and identified a novel function of macrophages in Tfh cell induction. In addition, our results showed that the generation of Tfh cells driven by macrophages is dependent on cell–cell contact and the level of inducible costimulator ligand (ICOSL) on macrophages which is regulated by CD40–CD40L signaling. Our findings uncovered a previously unappreciated role for Tfh cells in liver pathology caused by S. japonicum infection in mice.
Highlights
Schistosomiasis remains a major public health problem in many developing countries in tropical and subtropical regions, which affects approximately 200 million people worldwide [1,2]
After S. japonicum infection, parasite eggs are trapped in host liver and granulomas are induced to form around eggs
We show that Tfh cells play a novel role of promoting the hepatic granuloma formation and liver injury, and identified a novel function of macrophages in Tfh cells induction in S. japonicum-infected mouse model
Summary
Schistosomiasis remains a major public health problem in many developing countries in tropical and subtropical regions, which affects approximately 200 million people worldwide [1,2]. CD4+ T cell response induced by egg antigens orchestrates the development of granulomatous lesions around individual eggs in host liver [3]. Naıve CD4+ helper T (Th) cells recognize schistosome egg antigens presented by antigen-presenting cells (APCs) to differentiate into distinct effector subsets. These include Th1, Th2, and Th17 cells or regulatory T (Treg) cells, which differentiate under specific cytokine milieu. These populations express chemokine receptors for their homing to liver and produce distinct profiles of effector cytokines, which play roles in liver granuloma formation and regulation. Th2 and Th17 cells were reported to upregulate hepatic granuloma formation by secreting IL-4 and IL-17 respectively [4,5,6], while Th1 and Treg cells were reported to downregulate hepatic granuloma formation [5,7]
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