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ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut

Author

Listed:
  • Mengze Lyu

    (Cornell University
    Cornell University
    Cornell University)

  • Hiroaki Suzuki

    (Cornell University
    Cornell University
    Cornell University
    EA Pharma)

  • Lan Kang

    (Cornell University
    Cornell University
    Cornell University)

  • Fabrina Gaspal

    (University of Birmingham)

  • Wenqing Zhou

    (Cornell University
    Cornell University
    Cornell University)

  • Jeremy Goc

    (Cornell University
    Cornell University
    Cornell University)

  • Lei Zhou

    (Cornell University
    Cornell University
    Cornell University)

  • Jordan Zhou

    (Cornell University
    Cornell University
    Cornell University)

  • Wen Zhang

    (Cornell University
    Cornell University
    Cornell University)

  • Zeli Shen

    (Massachusetts Institute of Technology)

  • James G. Fox

    (Massachusetts Institute of Technology)

  • Robbyn E. Sockolow

    (Cornell University)

  • Terri M. Laufer

    (University of Pennsylvania
    Philadelphia Veterans Affairs Medical Center)

  • Yong Fan

    (Allegheny Health Network)

  • Gerard Eberl

    (Institut Pasteur)

  • David R. Withers

    (University of Birmingham)

  • Gregory F. Sonnenberg

    (Cornell University
    Cornell University
    Cornell University)

Abstract

Microbial colonization of the mammalian intestine elicits inflammatory or tolerogenic T cell responses, but the mechanisms controlling these distinct outcomes remain poorly understood, and accumulating evidence indicates that aberrant immunity to intestinal microbiota is causally associated with infectious, inflammatory and malignant diseases1–8. Here we define a critical pathway controlling the fate of inflammatory versus tolerogenic T cells that respond to the microbiota and express the transcription factor RORγt. We profiled all RORγt+ immune cells at single-cell resolution from the intestine-draining lymph nodes of mice and reveal a dominant presence of T regulatory (Treg) cells and lymphoid tissue inducer-like group 3 innate lymphoid cells (ILC3s), which co-localize at interfollicular regions. These ILC3s are distinct from extrathymic AIRE-expressing cells, abundantly express major histocompatibility complex class II, and are necessary and sufficient to promote microbiota-specific RORγt+ Treg cells and prevent their expansion as inflammatory T helper 17 cells. This occurs through ILC3-mediated antigen presentation, αV integrin and competition for interleukin-2. Finally, single-cell analyses suggest that interactions between ILC3s and RORγt+ Treg cells are impaired in inflammatory bowel disease. Our results define a paradigm whereby ILC3s select for antigen-specific RORγt+ Treg cells, and against T helper 17 cells, to establish immune tolerance to the microbiota and intestinal health.

Suggested Citation

  • Mengze Lyu & Hiroaki Suzuki & Lan Kang & Fabrina Gaspal & Wenqing Zhou & Jeremy Goc & Lei Zhou & Jordan Zhou & Wen Zhang & Zeli Shen & James G. Fox & Robbyn E. Sockolow & Terri M. Laufer & Yong Fan & , 2022. "ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut," Nature, Nature, vol. 610(7933), pages 744-751, October.
  • Handle: RePEc:nat:nature:v:610:y:2022:i:7933:d:10.1038_s41586-022-05141-x
    DOI: 10.1038/s41586-022-05141-x
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    Cited by:

    1. Elvira Mennillo & Yang Joon Kim & Gyehyun Lee & Iulia Rusu & Ravi K. Patel & Leah C. Dorman & Emily Flynn & Stephanie Li & Jared L. Bain & Christopher Andersen & Arjun Rao & Stanley Tamaki & Jessica T, 2024. "Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Chao Huang & Wenting Zhu & Qing Li & Yuchen Lei & Xi Chen & Shaorui Liu & Dianyu Chen & Lijian Zhong & Feng Gao & Shujie Fu & Danyang He & Jinsong Li & Heping Xu, 2024. "Antibody Fc-receptor FcεR1γ stabilizes cell surface receptors in group 3 innate lymphoid cells and promotes anti-infection immunity," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Jiacheng Hao & Chang Liu & Zhijie Gu & Xuanming Yang & Xun Lan & Xiaohuan Guo, 2024. "Dysregulation of Wnt/β-catenin signaling contributes to intestinal inflammation through regulation of group 3 innate lymphoid cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Adélaïde Gélineau & Geneviève Marcelin & Melissa Ouhachi & Sébastien Dussaud & Lise Voland & Raoul Manuel & Ines Baba & Christine Rouault & Laurent Yvan-Charvet & Karine Clément & Roxane Tussiwand & T, 2024. "Fructooligosaccharides benefits on glucose homeostasis upon high-fat diet feeding require type 2 conventional dendritic cells," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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