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The main clinically important species <jats:italic>Schistosoma mansoni<\/jats:italic> (<jats:italic>S.\u00a0mansoni<\/jats:italic>) and <jats:italic>Schistosoma japonicum<\/jats:italic> (<jats:italic>S.\u00a0japonicum<\/jats:italic>) cause inflammatory responses against tissue\u2010trapped eggs, resulting in formation of granulomas mainly in host liver. Persistent granulomatous response results in severe fibrosis in the liver, leading to irreversible impairment of the liver and even death of the host. CD1d, a highly conserved MHC class I\u2010like molecule, is expressed by both haematopoietic and non\u2010haematopoietic cells. CD1d on antigen\u2010presenting cells (APCs) of haematopoietic origin presents pathogen\u2010derived lipid antigens to natural killer T (NKT) cells, which enables them to rapidly produce large amounts of various cytokines and facilitate CD4<jats:sup>+<\/jats:sup> T helper (Th) cell differentiation upon invading pathogens. Noteworthy, hepatocytes of non\u2010haematopoietic origin have recently been shown to be involved in maintaining liver NKT cell homeostasis through a CD1d\u2010dependent manner. However, whether hepatocyte CD1d\u2010dependent regulation of NKT cell homeostasis also modulates CD4<jats:sup>+<\/jats:sup> Th cell responses and liver immunopathology in murine schistosomiasis remains to be addressed. Here, we show in mice that CD1d expression on hepatocytes was decreased dramatically upon <jats:italic>S.\u00a0japonicum<\/jats:italic> infection, accompanied by increased NKT cells, as well as upregulated Th1 and Th2 responses. Overexpression of CD1d in hepatocytes significantly decreased local NKT numbers and cytokines (IFN\u2010\u03b3, IL\u20104, IL\u201013), concomitantly with downregulation of both Th1 and Th2 responses and alleviation in pathological damage in livers of <jats:italic>S.\u00a0japonicum<\/jats:italic>\u2010infected mice. These findings highlight the potential of hepatocyte CD1d\u2010targeted therapies for liver immunopathology control in schistosomiasis.<\/jats:p>","DOI":"10.1111\/imm.13288","type":"journal-article","created":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T07:51:46Z","timestamp":1607327506000},"page":"328-338","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Hepatocyte CD1d protects against liver immunopathology in mice with schistosomiasis japonica"],"prefix":"10.1111","volume":"162","author":[{"given":"Zhigang","family":"Lei","sequence":"first","affiliation":[{"name":"Department of Pathogen Biology and Immunology Jiangsu Key Laboratory of Pathogen Biology Center for Global Health Nanjing Medical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pathogen Biology and Immunology 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