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CD200Rhigh neutrophils with dysfunctional autophagy establish systemic immunosuppression by increasing regulatory T cells

Cellular & Molecular Immunology volume 21, pages 349–361 (2024)Cite this article

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Abstract

Distinct neutrophil populations arise during certain pathological conditions. The generation of dysfunctional neutrophils during sepsis and their contribution to septicemia-related systemic immune suppression remain unclear. In this study, using an experimental sepsis model that features immunosuppression, we identified a novel population of pathogenic CD200Rhigh neutrophils that are generated during the initial stages of sepsis and contribute to systemic immune suppression by enhancing regulatory T (Treg) cells. Compared to their CD200Rlow counterparts, sepsis-generated CD200Rhigh neutrophils exhibit impaired autophagy and dysfunction, with reduced chemotactic migration, superoxide anion production, and TNF-α production. Increased soluble CD200 blocks autophagy and neutrophil maturation in the bone marrow during experimental sepsis, and recombinant CD200 treatment in vitro can induce neutrophil dysfunction similar to that observed in CD200Rhigh neutrophils. The administration of an α-CD200R antibody effectively reversed neutrophil dysfunction by enhancing autophagy and protecting against a secondary infection challenge, leading to increased survival. Transcriptome analysis revealed that CD200Rhigh neutrophils expressed high levels of Igf1, which elicits the generation of Treg cells, while the administration of an α-CD200R antibody inhibited Treg cell generation in a secondary infection model. Taken together, our findings revealed a novel CD200Rhigh neutrophil population that mediates the pathogenesis of sepsis-induced systemic immunosuppression by generating Treg cells.

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Acknowledgements

This work was supported by Basic Science Research Program (NRF-2020M3A9D3038435, NRF-2017R1A5A1014560) and the Korea Initiative for Fostering the University of Research and Innovation Program (NRF-2020M3H1A1077095) through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI22C2004).

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  1. Geon Ho Bae

    Present address: Division of Immunology, Boston Children’s Hospital, Boston, MA, USA

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  1. Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, Republic of Korea

    Ye Seon Kim, Yu Sun Jeong, Geon Ho Bae, Ji Hyeon Kang & Yoe-Sik Bae

  2. Department of Health Science and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, Republic of Korea

    Mingyu Lee & Yoe-Sik Bae

  3. Palo Alto Veterans Institute for Research, Veterans Affairs Hospital, Palo Alto, CA, 94304, USA

    Brian A. Zabel

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Y.K. designed and performed the research, analyzed the data, and wrote the paper. Y.J. designed and performed the research, analyzed data, and wrote the paper. G.B. designed the experiments and analyzed the data. J.K. performed the research and analyzed the data. M.L. designed the experiments and analyzed the data. B.A.Z. wrote the paper. Y.B. designed the research and wrote the paper.

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Correspondence to Yoe-Sik Bae.

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YSK, YSJ, and YSB have filed a patent related to this work. The other authors declare no competing interests.

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Kim, Y.S., Jeong, Y.S., Bae, G.H. et al. CD200Rhigh neutrophils with dysfunctional autophagy establish systemic immunosuppression by increasing regulatory T cells. Cell Mol Immunol 21, 349–361 (2024). https://doi.org/10.1038/s41423-024-01136-y

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