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

Liaoxun Lu
Tianhan Li
  • Function : Author
Xinyu Feng
  • Function : Author
Zhilong Liu
Yang Liu
  • Function : Author
Tianzhu Chao
Yanrong Gu
Rong Huang
Fanghui Zhang
  • Function : Author
Le He
Binhui Zhou
Eryan Kong
Zhuangzhuang Liu
  • Function : Author
Xugang Wang
  • Function : Author
Zhijun Chen
  • Function : Author
Hui Wang
  • Function : Author
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-03951950 , version 1 (23-01-2023)

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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, ⟨10.1371/journal.ppat.1010596⟩. ⟨hal-03951950⟩

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