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Prevention of T cell exhaustion by blockade of PD-1 results in clinical benefits to cancer patients and clearance of viral infections, however it remains largely unknown whether loss of PD-1 could prevent or cure schistosomiasis in susceptible mice. In this study, we found that<jats:italic>S<\/jats:italic>.<jats:italic>japonicum<\/jats:italic>infection dramatically induced PD-1 expression in T cells of the liver where the parasites chronically inhabit and elicit deadly inflammation. Even in mice infected by non-egg-producing unisex parasites, we still observed potent induction of PD-1 in liver T cells of C57BL\/6 mice following<jats:italic>S<\/jats:italic>.<jats:italic>japonicum<\/jats:italic>infection. To determine the function of PD-1 in schistosomiasis, we generated PD-1-deficient mice by CRISPR\/Cas9 and found that loss of PD-1 markedly increased T cell count in the liver and spleen of infected mice. IL-4 secreting Th2 cells were significantly decreased in the infected PD-1-deficient mice whereas IFN-\u03b3 secreting CD4<jats:sup>+<\/jats:sup>and CD8<jats:sup>+<\/jats:sup>T cells were markedly increased. Surprisingly, such beneficial changes of T cell response did not result in eradication of parasites or in lowering the pathogen burden. In further experiments, we found that loss of PD-1 resulted in both beneficial T cell responses and amplification of regulatory T cells that prevented PD-1-deficient T cells from unleashing anti-parasite activity. Moreover, such PD-1-deficient Tregs exert excessive immunosuppression and express larger amounts of adenosine receptors CD39 and CD73 that are crucial for Treg-mediated immunosuppression. Our experimental results have elucidated the function of PD-1 in schistosomiasis and provide novel insights into prevention and treatment of schistosomiasis on the basis of modulating host adaptive immunity.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010596","type":"journal-article","created":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T17:32:23Z","timestamp":1654536743000},"page":"e1010596","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["Excessive immunosuppression by regulatory T cells antagonizes T cell response to schistosome infection in PD-1-deficient 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