Th2 Cd4 + T Cells are Necessary and Sufficient for Schistosoma -Pulmonary Hypertension

Background: Inflammation 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: We 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. Parabiosis and Rag-/- mice reconstituted with CD4 T cells were used to determine the role of CD4 T cells.   Findings: We identified that embolization of Schistosoma eggs into the lungs of egg-sensitized mice increased the perivascular density of Th2 CD4+ T cells by recruitment of cells from the circulation, and triggered Type 2 inflammation. Parabiosis confirmed that egg embolization is required for the localized Type 2 immunity. We found Th2 CD4+ T cells were necessary for Schistosoma-induced PH, as deletion of CD4+ T cells or inhibiting their Th2 function protected against Type 2 inflammation and PH following Schistosoma exposure. We also observed adoptive transfer of Schistosoma-sensitized CD4+ Th2 cells was sufficient to drive Type 2 inflammation and PH. Interpretation: Th2 CD4+T cells are a necessary and sufficient component for the Type 2 inflammation-induced PH following Schistosoma exposure.   Funding Statement: Grant funding was provided by the American Heart Association Grants 17POST33670045 (RK), 19CDA34730030 (RK); NIH Grants P01HL014985 (RMT and BBG), R03HL133306 (BBG), and R01HL135872 (BBG). Ministerio de Economia y Competitividad (SAF2016-77222-R to AC), with funds co-financed by ERDF (FEDER) Funds from the European Commission, “A way of making Europe”, and the Cardiovascular Medical Research and Education Fund (AC and GB). Declaration of Interests: The authors declare that no conflict of interest exists. Ethics Approval Statement: All animal studies were approved by the University of Colorado Institutional Animal Care and Use Committee.