Th2 CD4 ⁺ T Cells Are Necessary and Sufficient for Schistosoma‐ Pulmonary Hypertension

Abstract

BackgroundInflammation underlies many forms of pulmonary hypertension (PH), including that resulting from Schistosoma infection, a major cause of PH worldwide. Schistosomiasis‐associated PH is proximately triggered by embolization of parasite eggs into the lungs, resulting in localized type 2 inflammation. However, the role of CD4+ T cells in this disease is not well defined.Methods and ResultsWe used a mouse model of schistosomiasis‐associated PH, induced by intraperitoneal egg sensitization followed by intravenous egg challenge, with outcomes including right ventricle systolic pressure measured by cardiac catheterization, and cell density and phenotype assessed by flow cytometry. We identified that embolization of Schistosoma eggs into lungs of egg‐sensitized mice increased the perivascular density of T‐helper 2 (Th2) CD4+ T cells by recruitment of cells from the circulation and triggered type 2 inflammation. Parabiosis confirmed that egg embolization is required for localized type 2 immunity. We found Th2 CD4+ T cells were necessary for Schistosoma‐induced PH, given that deletion of CD4+ T cells or inhibiting their Th2 function protected against type 2 inflammation and PH following Schistosoma exposure. We also observed that adoptive transfer of Schistosoma‐sensitized CD4+ Th2 cells was sufficient to drive type 2 inflammation and PH.ConclusionsTh2 CD4+ T cells are a necessary and sufficient component for the type 2 inflammation‐induced PH following Schistosoma exposure.

Schistosomiasis Pulmonary Arterial Hypertension

“…Many studies have started to dissect the immunological events that underlie SchPH pathogenesis (1,61,87,89,92,96,97,(103)(104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114). The current understanding of the signaling events is summarized in Figure 6.…”

“…In this model, the experimental mice are first intraperitoneally (IP) sensitized with Schistosoma eggs, which primes the immune cells. Two weeks later, the sensitized mice are intravenously (IV) challenged with Schistosoma eggs administered by tail vein injection, which results in a bolus of eggs embolizing into the lungs driving localized type 2 immunity ( 97 ). RHC and histological analysis is then performed seven days after intravenous challenge.…”

“…Complement activation may also be critical. Egg antigens are subsequently presented by antigen presenting cells (APCs) like dendritic cells to CD4 T cells, resulting in the production of Th2 inflammatory cytokines including IL-4 and IL-13 ( 97 , 108 ). Other cells such as eosinophils and basophils are present and may contribute to production of these cytokines, but in the liver fibrosis model eosinophils and basophils are dispensable ( 116 , 117 ) so they may well be dispensable in the lungs and SchPH pathogenesis as well.…”

Th2 Cd4 ⁺ T Cells are Necessary and Sufficient for <i>Schistosoma</i>-Pulmonary Hypertension

“…37 Given that both human immunodeficiency virus and Schistosoma are triggers of PAH, it is possible that dually infected individuals will have a higher prevalence of PAH, and in line with this hypothesis is the observation that there is a higher prevalence of liver disease complicating schistosomiasis in dually infected individuals, as compared with those infected with Schistosoma alone. 38 Alternatively, it is possible that the immune suppression resulting from human immunodeficiency virus infection could block the type 2 immunity required for Schistosoma-induced PH as shown here.…”

ICOS enhances follicular T helper responses and deteriorates the pathogenic process of liver in mice infected withSchistosoma japonicum

“…More importantly, continual pathogenic process of inflammation and fibrosis in the liver usually impairs its function, even leading to cirrhosis and live failure. Although previous studies have shown that antigen-specific T cells, such as Th2 and Th17, participate in the pathogenic process and Th1 and regulatory T cells (Tregs) antagonize Schistosomiasis -related inflammation [3-5]. The molecular mechanisms of immunoregulation of S. japonicum infection-related inflammation and fibrosis in the liver have been incompletely clarified.…”