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Induction and transcriptional regulation of the co-inhibitory gene module in T cells

Author

Listed:
  • Norio Chihara

    (Harvard Medical School and Brigham and Women’s Hospital)

  • Asaf Madi

    (Harvard Medical School and Brigham and Women’s Hospital
    Broad Institute of MIT and Harvard)

  • Takaaki Kondo

    (Harvard Medical School and Brigham and Women’s Hospital)

  • Huiyuan Zhang

    (Harvard Medical School and Brigham and Women’s Hospital)

  • Nandini Acharya

    (Harvard Medical School and Brigham and Women’s Hospital)

  • Meromit Singer

    (Broad Institute of MIT and Harvard)

  • Jackson Nyman

    (Broad Institute of MIT and Harvard)

  • Nemanja D. Marjanovic

    (Broad Institute of MIT and Harvard)

  • Monika S. Kowalczyk

    (Broad Institute of MIT and Harvard
    Celsius Therapeutics)

  • Chao Wang

    (Harvard Medical School and Brigham and Women’s Hospital)

  • Sema Kurtulus

    (Harvard Medical School and Brigham and Women’s Hospital)

  • Travis Law

    (Broad Institute of MIT and Harvard)

  • Yasaman Etminan

    (Harvard Medical School and Brigham and Women’s Hospital)

  • James Nevin

    (Harvard Medical School and Brigham and Women’s Hospital)

  • Christopher D. Buckley

    (Rheumatology Research Group, Center for Translational Inflammation Research, Queen Elizabeth Hospital)

  • Patrick R. Burkett

    (Harvard Medical School and Brigham and Women’s Hospital
    Brigham and Women’s Hospital)

  • Jason D. Buenrostro

    (Broad Institute of MIT and Harvard)

  • Orit Rozenblatt-Rosen

    (Broad Institute of MIT and Harvard)

  • Ana C. Anderson

    (Harvard Medical School and Brigham and Women’s Hospital
    Broad Institute of MIT and Harvard)

  • Aviv Regev

    (Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology
    Koch Institute and Ludwig Center, Massachusetts Institute of Technology)

  • Vijay K. Kuchroo

    (Harvard Medical School and Brigham and Women’s Hospital
    Broad Institute of MIT and Harvard)

Abstract

The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of co-inhibitory receptors on CD4+ T cells promotes autoimmunity, whereas sustained overexpression on CD8+ T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and diseases such as cancer1,2. Here, using RNA and protein expression profiling at single-cell resolution in mouse cells, we identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but also many new surface receptors. We functionally validated two new co-inhibitory receptors, activated protein C receptor (PROCR) and podoplanin (PDPN). The module of co-inhibitory receptors is co-expressed in both CD4+ and CD8+ T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in several physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors PRDM1 and c-MAF as cooperative regulators of the co-inhibitory module, and this was validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumour immunity.

Suggested Citation

  • Norio Chihara & Asaf Madi & Takaaki Kondo & Huiyuan Zhang & Nandini Acharya & Meromit Singer & Jackson Nyman & Nemanja D. Marjanovic & Monika S. Kowalczyk & Chao Wang & Sema Kurtulus & Travis Law & Ya, 2018. "Induction and transcriptional regulation of the co-inhibitory gene module in T cells," Nature, Nature, vol. 558(7710), pages 454-459, June.
    • Handle: RePEc:nat:nature:v:558:y:2018:i:7710:d:10.1038_s41586-018-0206-z
    DOI: 10.1038/s41586-018-0206-z
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    Cited by:

    1. Hao Li & Zebei Han & Yu Sun & Fu Wang & Pengzhen Hu & Yuang Gao & Xuemei Bai & Shiyu Peng & Chao Ren & Xiang Xu & Zeyu Liu & Hebing Chen & Yang Yang & Xiaochen Bo, 2024. "CGMega: explainable graph neural network framework with attention mechanisms for cancer gene module dissection," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Alexandra Argyriou & Marc H. Wadsworth & Adrian Lendvai & Stephen M. Christensen & Aase H. Hensvold & Christina Gerstner & Annika Vollenhoven & Kellie Kravarik & Aaron Winkler & Vivianne Malmström & K, 2022. "Single cell sequencing identifies clonally expanded synovial CD4+ TPH cells expressing GPR56 in rheumatoid arthritis," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Sophie Hillion & Anjelica Miranda & Christelle Dantec & Marina Boudigou & Laëtitia Pottier & Divi Cornec & Raul M. Torres & Roberta Pelanda, 2024. "Maf expression in B cells restricts reactive plasmablast and germinal center B cell expansion," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Leticia Laura Niborski & Paul Gueguen & Mengliang Ye & Allan Thiolat & Rodrigo Nalio Ramos & Pamela Caudana & Jordan Denizeau & Ludovic Colombeau & Raphaël Rodriguez & Christel Goudot & Jean-Michel Lu, 2022. "CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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