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Follicular regulatory T cells restrain kidney allograft rejection in mice by suppressing alloreactive B cells

Author

Listed:
  • Hengcheng Zhang

    (Harvard Medical School)

  • Manuel A. Podestà

    (Harvard Medical School)

  • Cecilia B. Cavazzoni

    (Harvard Medical School)

  • Yumeng Wu

    (Harvard Medical School)

  • Jeong-Mi Lee

    (Harvard Medical School)

  • Xiaofei Li

    (Harvard Medical School)

  • Paulo Lisboa Raeder

    (Harvard Medical School
    University of São Paulo)

  • Pragya Chandrakar

    (Harvard Medical School)

  • Maya Gempler

    (Harvard Medical School)

  • Sierra Richardson

    (Harvard Medical School)

  • Deepjyoti Ghosh

    (The University of Chicago)

  • Ismail Sayin

    (University of Chicago)

  • Bruce R. Blazar

    (University of Minnesota)

  • Reza Abdi

    (Harvard Medical School)

  • Astrid Weins

    (Harvard Medical School)

  • Anita S. Chong

    (University of Chicago)

  • Peter T. Sage

    (Harvard Medical School)

Abstract

Pathogenic antibodies produced by alloreactive B cells mediate antibody-mediated rejection after kidney transplantation, but the mechanisms remain poorly understood. Follicular regulatory T (Tfr) cells modulate follicular helper T cell-mediated B cell responses, but the functions of Tfr in controlling alloreactive antibody are unknown. Here we study the developmental signals and functions of Tfr cells in mouse allogeneic kidney transplantation models, and show that costimulatory blockade alters the development of Tfr cells disproportionately by decreasing germinal center (GC)-like Tfr cells but increasing follicular-like Tfr cells. Functionally, global Tfr cell deletion results in accelerated graft rejection and increases in donor-specific B cells in both draining lymph nodes and kidney allografts. Mechanistically, Tfr cell deletion increases GC B cell expression of pro-inflammatory cytokines such as IL-15, while neutralization of IL-15 compensates for the loss of Tfr cells and prolongs the survival of mice receiving kidney transplants. Together our preclinical mouse data demonstrate how Tfr restrains kidney allograft rejection by limiting alloreactive B cell responses.

Suggested Citation

  • Hengcheng Zhang & Manuel A. Podestà & Cecilia B. Cavazzoni & Yumeng Wu & Jeong-Mi Lee & Xiaofei Li & Paulo Lisboa Raeder & Pragya Chandrakar & Maya Gempler & Sierra Richardson & Deepjyoti Ghosh & Isma, 2025. "Follicular regulatory T cells restrain kidney allograft rejection in mice by suppressing alloreactive B cells," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57468-4
    DOI: 10.1038/s41467-025-57468-4
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    as
    1. Manuel A. Podestà & Cecilia B. Cavazzoni & Benjamin L. Hanson & Elsa D. Bechu & Garyfallia Ralli & Rachel L. Clement & Hengcheng Zhang & Pragya Chandrakar & Jeong-Mi Lee & Tamara Reyes-Robles & Reza A, 2023. "Stepwise differentiation of follicular helper T cells reveals distinct developmental and functional states," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Christoph Jandl & Sue M. Liu & Pablo F. Cañete & Joanna Warren & William E. Hughes & Alexis Vogelzang & Kylie Webster & Maria E. Craig & Gulbu Uzel & Alexander Dent & Polina Stepensky & Bärbel Keller , 2017. "IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
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