FOXP3+Regulatory T Cells in Hepatic Fibrosis and Splenomegaly Caused by Schistosoma japonicum: the Spleen May Be a Major Source of Tregs in Subjects with Splenomegaly

Schistosoma eggs cause chronic liver inflammation and a complex disease characterized by hepatic fibrosis (hf) and splenomegaly (splm). foxp3+tregs could regulate inflammation,but it is unclear where these cells are produced and what roles they play in human schistosomiasis. we investigated blood and spleen foxp3+tregs in chinese fishermen with lifelong exposure to schistosoma japonicum and various degrees of liver and spleen disease. foxp3+tregs accounted for 4.3% of cd4+t cells and 41.2% of foxp3+cd4+t cells; they could be divided into cd45ra-foxp3hieffector (etregs) and cd45ra+foxp3lownaive tregs. blood treg levels were high in severe hf (+1.3; p = 0.004) and in splm (+1.03,p = 0.03). multivariate regression showed that severe hf (+0.85,p = 0.01) and splm (+0.97; p = 0.05) were independently associated with the higher proportion of tregs in the blood. this effect was mostly due to an increase in the proportion of etregs in the blood of hf+++(+0.9%; p = 0.04) and splm (+0.9%; p = 0.04) patients. the proportion of etregs expressing cxcr3 in the blood was lower in the hf+++patients (37.4 +/- 5.9%) than in those with milder fibrosis (51.7 ± 2%; p = 0.009),whereas proportion were similar for cells expressing cd25hi,ccr7,and ctla-4. splenectomy improves symptoms and was associated with decreases in blood foxp3+treg (-2.5; p<0.001) and etreg (-1.3; p = 0.03) levels. splm spleens contained a high proportion of etregs with cxcr3,ccr5 and ctla4 upregulation and ccr7 downregulation. this,and the strong expression of ligands of cxcr3 and ccr5 in the liver (n = 8) but not in the spleen suggested that spleen etregs migrated to th1-infiltrated liver tissues. such migration may be attenuated in hepatosplenic patients due to lower levels of cxcr3 expression on tregs (p = 0.009). thus,higher blood treg levels are associated with severe liver disease and splenomegaly. our data are consistent with the hypothesis that the spleen is a major source of tregs in subjects with splenomegaly. in most cases,tregs migrate to the th1-infiltrated liver and the lower levels of cxcr3+tregs in the blood of patients with severe schistosomiasis suggest that decreases in treg migration sites of inflammation may aggravate the disease. © 2016 romano et al.