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CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner

Author

Listed:
  • Jonathan W. Lo

    (Imperial College London)

  • Jan-Hendrik Schroeder

    (King’s College London)

  • Luke B. Roberts

    (King’s College London
    University of Manchester)

  • Rami Mohamed

    (King’s College London)

  • Domenico Cozzetto

    (Imperial College London)

  • Gordon Beattie

    (University College London
    University College London)

  • Omer S. Omer

    (King’s College London)

  • Ellen M. Ross

    (Royal Free Campus)

  • Frank Heuts

    (Royal Free Campus)

  • Geraldine M. Jowett

    (King’s College London
    King’s College London
    King’s College London)

  • Emily Read

    (King’s College London)

  • Matthew Madgwick

    (Imperial College London
    Norwich Research Park
    Norwich Research Park)

  • Joana F. Neves

    (King’s College London)

  • Tamas Korcsmaros

    (Imperial College London
    Norwich Research Park
    Norwich Research Park)

  • Richard G. Jenner

    (University College London)

  • Lucy S. K. Walker

    (Royal Free Campus)

  • Nick Powell

    (Imperial College London)

  • Graham M. Lord

    (King’s College London
    University of Manchester)

Abstract

The maintenance of intestinal homeostasis is a fundamental process critical for organismal integrity. Sitting at the interface of the gut microbiome and mucosal immunity, adaptive and innate lymphoid populations regulate the balance between commensal micro-organisms and pathogens. Checkpoint inhibitors, particularly those targeting the CTLA-4 pathway, disrupt this fine balance and can lead to inflammatory bowel disease and immune checkpoint colitis. Here, we show that CTLA-4 is expressed by innate lymphoid cells and that its expression is regulated by ILC subset-specific cytokine cues in a microbiota-dependent manner. Genetic deletion or antibody blockade of CTLA-4 in multiple in vivo models of colitis demonstrates that this pathway plays a key role in intestinal homeostasis. Lastly, we have found that this observation is conserved in human IBD. We propose that this population of CTLA-4-positive ILC may serve as an important target for the treatment of idiopathic and iatrogenic intestinal inflammation.

Suggested Citation

  • Jonathan W. Lo & Jan-Hendrik Schroeder & Luke B. Roberts & Rami Mohamed & Domenico Cozzetto & Gordon Beattie & Omer S. Omer & Ellen M. Ross & Frank Heuts & Geraldine M. Jowett & Emily Read & Matthew M, 2024. "CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51719-6
    DOI: 10.1038/s41467-024-51719-6
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    References listed on IDEAS

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    1. Krista Dubin & Margaret K. Callahan & Boyu Ren & Raya Khanin & Agnes Viale & Lilan Ling & Daniel No & Asia Gobourne & Eric Littmann & Curtis Huttenhower & Eric G. Pamer & Jedd D. Wolchok, 2016. "Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis," Nature Communications, Nature, vol. 7(1), pages 1-8, April.
    2. Jonathan W. Lo & Domenico Cozzetto & James L. Alexander & Nathan P. Danckert & Matthew Madgwick & Naomi Knox & Jillian Yong Xin Sieh & Marton Olbei & Zhigang Liu & Hajir Ibraheim & Jesus Miguens Blanc, 2023. "Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Sofia Buonocore & Philip P. Ahern & Holm H. Uhlig & Ivaylo I. Ivanov & Dan R. Littman & Kevin J. Maloy & Fiona Powrie, 2010. "Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology," Nature, Nature, vol. 464(7293), pages 1371-1375, April.
    4. David Artis & Hergen Spits, 2015. "The biology of innate lymphoid cells," Nature, Nature, vol. 517(7534), pages 293-301, January.
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