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Modulation of plasmacytoid dendritic cell and CD4+ T cell differentiation accompanied by upregulation of the cholinergic anti-inflammatory pathway induced by enterovirus 71

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Abstract

Enterovirus 71 (EV71) is a neurotropic enterovirus associated with hand, foot, and mouth disease (HFMD) fatalities. In this study, we investigated the impact of EV71 on plasmacytoid dendritic cells (pDCs) and CD4+ T cells. The results showed that pDCs were promptly activated, secreting interferon (IFN)-α and inducing CD4+ T cell proliferation and differentiation during early EV71 infection. This initiated adaptive immune responses and promoted proinflammatory cytokine production by CD4+ T cells. Over time, viral nucleic acids and proteins were synthesized in pDCs and CD4+ T cells. Concurrently, the cholinergic anti-inflammatory pathway (CAP) was activated, exhibiting an anti-inflammatory role. With constant viral stimulation, pDCs and CD4+ T cells showed reduced differentiation and cytokine secretion. Defects in pDCs were identified as a key factor in CD4+ T cell tolerance. CAP had a more significant regulatory effect on CD4+ T cells than on pDCs and was capable of inhibiting inflammation in these cells.

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Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

EV71:

Enterovirus 71

HFMD:

Hand, foot, and mouth disease

pDC:

Plasmacytoid dendritic cell

CAP:

Cholinergic anti-inflammatory pathway

IFN:

Interferon

IL:

Interleukin

G-CSF:

Granulocyte-colony stimulating factor

TNF:

Tumor necrosis factor

ChAT:

Choline acetyltransferase

AChE:

Acetylcholinesterase

nAChR:

Nicotinic acetylcholine receptor

PBMC:

Peripheral blood mononuclear cell

PBS:

Phosphate-buffered saline

CTAB-QD:

CTAB-modified quantum dot

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Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81960294 and 82060192), the Yunnan International Science and Technology Cooperation of Allergic Disease (202103AF140008), the Yunnan Basic Research Project (202101AT070231), the Yunnan Young and Middle-Aged Academic and Technical Leaders (Reserve) Project (202105AC160012), the Yunnan High-Level Health Technical Personnel Training Program (D-2019017), and the Kunming Health Science and Technology Personnel Training Project (2020-SW-11).

Author information

Author notes

  1. Li Li, Rong-Wei Huang, Xiao-Ning Liu, Xiao-Yi Xiang and Yuan-Tao Zhou have contributed equally to this work.

Authors and Affiliations

  1. Yunnan Medical Center for Pediatric Diseases, Yunnan Institute of Pediatrics, Kunming Children’s Hospital, Kunming, 650228, Yunnan, China

    Li Li, Lv-Yuan Tao & Jia Yu

  2. Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children’s Major Disease Research, Yunnan Province Clinical Research Center for Children’s Health and Disease, Kunming, 650228, Yunnan, China

    Li Li, Rong-Wei Huang, Xiao-Yi Xiang, Yuan-Tao Zhou, Lv-Yuan Tao & Xiao-Mei Liu

  3. Department of 2nd Infection, Kunming Children’s Hospital, Zouping People’s Hospital, Kunming, 650228, Yunnan, China

    Yan-Chun Wang

  4. Department of Clinical Laboratory, Kunming Children’s Hospital, Kunming, 650228, Yunnan, China

    Xing-Xing Feng

  5. Department of Clinical Laboratory, Zouping People’s Hospital, Binzhou, 256200, Shandong, China

    Qin Yi

  6. Department of Pharmacy, Kunming Children’s Hospital, Kunming, 650228, Yunnan, China

    Xiao-Ning Liu

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Contributions

Li Li participated in study design, analysis and interpretation of results, manuscript preparation, data collection and processing, and statistical analysis. Rongwei Huang, XiaoNing Liu and Xiaoyi Xiang participated in data collection and processing. Yuantao Zhou, Xingxing Feng, Lvyuan Tao, Jia Yu, Qin Yi, Yanchun Wang, and Xiaomei Liu participated in sample collection and processing. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xiao-Mei Liu.

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Ethical approval and consent to participate

All of the clinical samples used in this study were remaining human blood samples that had been collected by the Clinical Laboratory Department of Kunming Children's Hospital. Ethical approval for the study was given by the Ethics Committee of Kunming Children's Hospital.

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The authors declare that they have no competing interests.

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Li, L., Huang, RW., Liu, XN. et al. Modulation of plasmacytoid dendritic cell and CD4+ T cell differentiation accompanied by upregulation of the cholinergic anti-inflammatory pathway induced by enterovirus 71. Arch Virol 169, 73 (2024). https://doi.org/10.1007/s00705-024-05974-z

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