{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T15:15:59Z","timestamp":1790694959498,"version":"4.1.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"name":"Canadian Institutes for Health Research and Research Manitoba"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,2]]},"abstract":"<jats:p>Visceral leishmaniasis (VL) is associated with severe immune dysfunction and if untreated leads to death. Because the liver is one of the primary target organs in VL, unraveling the mechanisms governing the local hepatic immune response is important for understanding the immunopathogenesis of VL. We previously reported that mice with inactivating knockin mutation in the p110\u03b4 gene (p110\u03b4<jats:sup>D910A<\/jats:sup>) are resistant to VL, due in part to impaired regulatory T\u2010cell (Treg) expansion. In this study, we investigated the mechanism of this resistance by focusing on hepatic stellate cells (HSCs), which are known to regulate Treg induction and expansion. We show that HSCs are infected with<jats:italic toggle=\"yes\">Leishmania donovani in vivo<\/jats:italic>and<jats:italic toggle=\"yes\">in vitro<\/jats:italic>and that this infection leads to the production of interleukin\u20102, interleukin\u20106, and transforming growth factor\u2010\u03b2, cytokines known to induce Tregs. We further demonstrate that<jats:italic toggle=\"yes\">L. donovani<\/jats:italic>infection leads to expansion of HSCs in a p110\u03b4\u2010dependent manner and that this correlated with proliferation of hepatic Tregs<jats:italic toggle=\"yes\">in vivo<\/jats:italic>.<jats:italic toggle=\"yes\">In vitro<\/jats:italic>studies clearly show that<jats:italic toggle=\"yes\">L. donovani<\/jats:italic>\u2013infected HSCs induce CD4<jats:sup>+<\/jats:sup>T cells to become Tregs and expand Tregs in a p110\u03b4\u2010dependent manner. Targeted depletion of HSCs during infection caused a dramatic reduction in liver Treg numbers and proliferation, which was associated with a decrease in interleukin\u201010 production by hepatic T cells and a more efficient parasite control.<jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: These results demonstrate the critical role of HSCs in the pathogenesis of VL and suggest that the enhanced resistance of p110\u03b4<jats:sup>D910A<\/jats:sup>mice to<jats:italic toggle=\"yes\">L. donovani<\/jats:italic>infection is due in part to impaired expansion and inability of their HSCs to induce and expand Tregs in the liver. (H<jats:sc>epatology<\/jats:sc>2016;63:620\u2013632)<\/jats:p>","DOI":"10.1002\/hep.28130","type":"journal-article","created":{"date-parts":[[2015,8,20]],"date-time":"2015-08-20T07:26:52Z","timestamp":1440055612000},"page":"620-632","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":25,"title":["Hepatic stellate cells regulate liver immunity to visceral leishmaniasis through P110\u03b4\u2010dependent induction and expansion of regulatory T cells in mice"],"prefix":"10.1097","volume":"63","author":[{"given":"Forough","family":"Khadem","sequence":"first","affiliation":[{"name":"Department of Immunology, Faculty of Medicine,University of Manitoba,Winnipeg,Manitoba,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine,University of 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