Abstract: TH-OR104
T Follicular Regulatory Cells Restrain Alloimmunity through Limiting Proinflammatory Cytokines in B Cells
Session Information
- Transplantation: Basic and Translational Advances
October 24, 2024 | Location: Room 25, Convention Center
Abstract Time: 05:10 PM - 05:20 PM
Category: Transplantation
- 2101 Transplantation: Basic
Authors
- Zhang, Hengcheng, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Podestà, Manuel Alfredo, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Bataglioli Cavazzoni, Cecilia, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Lee, Jeong-Mi, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Raeder, Paulo Lisboa, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Chandrakar, Pragya, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Gempler, Maya Grace, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Ghosh, Deepjyoti, The University of Chicago, Chicago, Illinois, United States
- Sayin, Ismail, The University of Chicago, Chicago, Illinois, United States
- Chong, Anita S., The University of Chicago, Chicago, Illinois, United States
- Sage, Peter, Brigham and Women's Hospital, Boston, Massachusetts, United States
Background
Pathogenic antibodies produced by alloreactive B cells mediate antibody-mediated rejection (ABMR) after kidney transplantation. Follicular regulatory T (Tfr) cells modulate Tfh cell-mediated B cell responses but their roles in controlling ABMR are unknown.
Methods
Mouse models of kidney transplantation were performed. The transcriptional program and TCR clonality of Tfr cells were assessed by single-cell sequencing. Selective elimination of Tfr in mice was used to dissect the function. Donor-specific antibody (DSA) test and histology were used to monitor ABMR. I-E tetramer and a single B cell culture detected the germinal center (GC) responses. Bulk RNA-seq analyzed GC B cells to investigate transcriptional programming regulated by Tfr cells and its mechanism.
Results
Tfr cells differentiate after allogeneic transplantation and undergo development through three distinct stages. Clinical immunosuppression alters the development and disproportionately skews the subsets by decreasing GC-like Tfr cells and increasing follicular-like Tfr cells. Functionally, Tfr cell deletion early, but not late, after transplantation results in accelerated rejection and increases in alloreactive B cell clones, DSA, and ABMR leading to reduced recipient survival. At the GC level, deletion of Tfr cells results in B cells with enhanced pathogenic potential which are marked by increased production of proinflammatory cytokines IL-15. Neutralization of IL-15 rescued the accelerated rejection with Tfr deletion and prolonged survival.
Conclusion
Tfr cells are key regulators of kidney transplant ABMR with unique development signals and regulate alloimmunity by suppressing donor-specific GC B cells from the early stages of kidney transplantation.
Funding
- Other NIH Support