Excessive immunosuppression by regulatory T cells antagonizes T cell response to schistosome infection in PD-1-deficient mice - Archive ouverte HAL Access content directly
Journal Articles PLoS Pathogens Year : 2022

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

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Liaoxun Lu
Zhilong Liu
Tianzhu Chao
Yanrong Gu
Rong Huang
Le He
Binhui Zhou
Eryan Kong
Lichen Zhang
Yinming Liang

Abstract

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.
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Dates and versions

hal-03933579 , version 1 (10-01-2023)

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Cite

Liaoxun Lu, Tianhan Li, Xinyu Feng, Zhilong Liu, Yang Liu, et al.. Excessive immunosuppression by regulatory T cells antagonizes T cell response to schistosome infection in PD-1-deficient mice. PLoS Pathogens, 2022, 18 (6), pp.e1010596. ⟨10.1371/journal.ppat.1010596⟩. ⟨hal-03933579⟩

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