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Lymphotoxin limits Foxp3+ regulatory T cell development from Foxp3lo precursors via IL-4 signaling

Author

Listed:
  • Alexia Borelli

    (Turing Centre for Living Systems)

  • Jérémy C. Santamaria

    (Turing Centre for Living Systems)

  • Cloé Zamit

    (Turing Centre for Living Systems)

  • Cécile Apert

    (INSERM UMR1291—CNRS UMR5051—University Toulouse III
    Institut Pasteur)

  • Jessica Chevallier

    (Turing Centre for Living Systems)

  • Philippe Pierre

    (Turing Centre for Living Systems)

  • Rafael J. Argüello

    (Turing Centre for Living Systems)

  • Lionel Spinelli

    (Turing Centre for Living Systems)

  • Magali Irla

    (Turing Centre for Living Systems)

Abstract

Regulatory T cells (Treg) are critical players of immune tolerance that develop in the thymus via two distinct developmental pathways involving CD25+Foxp3− and CD25−Foxp3lo precursors. However, the mechanisms regulating the recently identified Foxp3lo precursor pathway remain unclear. Here, we find that the membrane-bound lymphotoxin α1β2 (LTα1β2) heterocomplex is upregulated during Treg development upon TCR/CD28 and IL-2 stimulation. We show that Lta expression limits the maturational development of Treg from Foxp3lo precursors by regulating their proliferation, survival, and metabolic profile. Transgenic reporter mice and transcriptomic analyses further reveal that medullary thymic epithelial cells (mTEC) constitute an unexpected source of IL-4. We demonstrate that LTα1β2-lymphotoxin β receptor-mediated interactions with mTEC limit Treg development by down-regulating IL-4 expression in mTEC. Collectively, our findings identify the lymphotoxin axis as the first inhibitory checkpoint of thymic Treg development that fine-tunes the Foxp3lo Treg precursor pathway by limiting IL-4 availability.

Suggested Citation

  • Alexia Borelli & Jérémy C. Santamaria & Cloé Zamit & Cécile Apert & Jessica Chevallier & Philippe Pierre & Rafael J. Argüello & Lionel Spinelli & Magali Irla, 2024. "Lymphotoxin limits Foxp3+ regulatory T cell development from Foxp3lo precursors via IL-4 signaling," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51164-5
    DOI: 10.1038/s41467-024-51164-5
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    1. Philippe Bouillet & Jared F. Purton & Dale I. Godfrey & Li-Chen Zhang & Leigh Coultas & Hamsa Puthalakath & Marc Pellegrini & Suzanne Cory & Jerry M. Adams & Andreas Strasser, 2002. "BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes," Nature, Nature, vol. 415(6874), pages 922-926, February.
    2. C. Colin Brinkman & Daiki Iwami & Molly K. Hritzo & Yanbao Xiong & Sarwat Ahmad & Thomas Simon & Keli L. Hippen & Bruce R. Blazar & Jonathan S. Bromberg, 2016. "Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration," Nature Communications, Nature, vol. 7(1), pages 1-16, November.
    3. Wong Yu & Hitoshi Nagaoka & Mila Jankovic & Ziva Misulovin & Heikyung Suh & Antonius Rolink & Fritz Melchers & Eric Meffre & Michel C. Nussenzweig, 1999. "Continued RAG expression in late stages of B cell development and no apparent re-induction after immunizion," Nature, Nature, vol. 400(6745), pages 682-687, August.
    4. Junyue Cao & Malte Spielmann & Xiaojie Qiu & Xingfan Huang & Daniel M. Ibrahim & Andrew J. Hill & Fan Zhang & Stefan Mundlos & Lena Christiansen & Frank J. Steemers & Cole Trapnell & Jay Shendure, 2019. "The single-cell transcriptional landscape of mammalian organogenesis," Nature, Nature, vol. 566(7745), pages 496-502, February.
    5. Suoqin Jin & Christian F. Guerrero-Juarez & Lihua Zhang & Ivan Chang & Raul Ramos & Chen-Hsiang Kuan & Peggy Myung & Maksim V. Plikus & Qing Nie, 2021. "Inference and analysis of cell-cell communication using CellChat," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
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