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

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, Ismail Sayin, Bruce R. Blazar, Reza Abdi, Astrid Weins, Anita S. Chong and Peter T. Sage ()
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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
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

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57468-4

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