Excessive immunosuppression by regulatory T cells antagonizes T cell response to schistosome infection in PD-1-deficient mice

• Published in: PLoS pathogens Vol. 18; no. 6; p. e1010596
• Main Authors: Lu, Liaoxun, Li, Tianhan, Feng, Xinyu, Liu, Zhilong, Liu, Yang, Chao, Tianzhu, Gu, Yanrong, Huang, Rong, Zhang, Fanghui, He, Le, Zhou, Binhui, Kong, Eryan, Liu, Zhuangzhuang, Wang, Xugang, Chen, Zhijun, Wang, Hui, Malissen, Marie, Malissen, Bernard, Zhang, Lichen, Liang, Yinming
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.06.2022; Public Library of Science (PLoS)
• Subjects: Adaptive immunity; Adenosine; Adenosine receptors; Antigens; Biology and Life Sciences; Cancer; CD4 antigen; CD73 antigen; CD8 antigen; Cell division; CRISPR; Eggs; Flatworms; Helper cells; Hepatocytes; Immunoregulation; Immunosuppression; Infections; Infectious diseases; Interleukin 4; Life Sciences; Liver; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Parasites; Pathogens; Pathology; PD-1 protein; Prevention; Research and Analysis Methods; Rodents; Schistosomiasis; Spleen; Tropical diseases; Viral infections; γ-Interferon
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1010596

Schistosomiasis is caused by parasitic flatworms known as schistosomes and affects over 200 million people worldwide. 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 S . japonicum 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 S . japonicum 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-γ secreting CD4 + and CD8 + 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.