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Ex vivo-expanded human CD19+TIM-1+ regulatory B cells suppress immune responses in vivo and are dependent upon the TIM-1/STAT3 axis

Author

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  • S. Shankar

    (University of Oxford
    University of Oxford)

  • J. Stolp

    (University of Oxford)

  • S. C. Juvet

    (University of Oxford)

  • J. Beckett

    (University of Oxford)

  • P. S. Macklin

    (University of Oxford)

  • F. Issa

    (University of Oxford)

  • J. Hester

    (University of Oxford)

  • K. J. Wood

    (University of Oxford)

Abstract

Regulatory B cells (Breg) are a heterogenous population with immune-modulating functions. The rarity of human IL-10+ Breg makes translational studies difficult. Here we report ex vivo expansion of human B cells with in vivo regulatory function (expBreg). CD154-stimulation of human CD19+ B cells drives >900-fold expansion of IL-10+ B cells that is maintained in culture for 14 days. Whilst expBreg-mediated suppressive function is partially dependent on IL-10 expression, CRISPR-mediated gene deletions demonstrate predominant roles for TIM-1 and CD154. TIM-1 regulates STAT3 signalling and modulates downstream suppressive function. In a clinically relevant humanised mouse model of skin transplantation, expBreg prolongs human allograft survival. Meanwhile, CD19+CD73-CD25+CD71+TIM-1+CD154+ Breg cells are enriched in the peripheral blood of human donors with cutaneous squamous cell carcinoma (SCC). TIM-1+ and pSTAT3+ B cells are also identified in B cell clusters within histological sections of human cutaneous SCC tumours. Our findings thus provide insights on Breg homoeostasis and present possible targets for Breg-related therapies.

Suggested Citation

  • S. Shankar & J. Stolp & S. C. Juvet & J. Beckett & P. S. Macklin & F. Issa & J. Hester & K. J. Wood, 2022. "Ex vivo-expanded human CD19+TIM-1+ regulatory B cells suppress immune responses in vivo and are dependent upon the TIM-1/STAT3 axis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30613-z
    DOI: 10.1038/s41467-022-30613-z
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    1. Md Mahmudul Hasan & Sumi Sukumaran Nair & Jacqueline G. O’Leary & LuAnn Thompson-Snipes & Verah Nyarige & Junwen Wang & Walter Park & Mark Stegall & Raymond Heilman & Goran B. Klintmalm & HyeMee Joo &, 2021. "Implication of TIGIT+ human memory B cells in immune regulation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Shabnam Shalapour & Joan Font-Burgada & Giuseppe Di Caro & Zhenyu Zhong & Elsa Sanchez-Lopez & Debanjan Dhar & Gerald Willimsky & Massimo Ammirante & Amy Strasner & Donna E. Hansel & Christina Jamieso, 2015. "Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy," Nature, Nature, vol. 521(7550), pages 94-98, May.
    3. Ping Shen & Toralf Roch & Vicky Lampropoulou & Richard A. O’Connor & Ulrik Stervbo & Ellen Hilgenberg & Stefanie Ries & Van Duc Dang & Yarúa Jaimes & Capucine Daridon & Rui Li & Luc Jouneau & Pierre B, 2014. "IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases," Nature, Nature, vol. 507(7492), pages 366-370, March.
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