Tfr Cells Restrain Rejection of Kidney Allografts by Limiting Pro-Inflammatory Cytokines in B cells [scRNA-seq]

Pathogenic antibodies produced by alloreactive B cells mediate antibody-mediated rejection (ABMR) after kidney transplantation, but the mechanisms controlling these antibodies remain poorly understood. Follicular Regulatory T (Tfr) cells modulate follicular helper T (Tfh) cell-mediated B cell responses but their roles in controlling alloreactive antibody are unknown. Here, we studied the developmental signals and functions of Tfr cells in allogeneic kidney transplantation. We show that costimulatory blockade alters the development of Tfr cells disproportionately by decreasing germinal center (GC)-like Tfr cells and increasing follicular-like Tfr cells. Functionally, Tfr cell deletion resulted in accelerated rejection and increases in donor-specific B cells in both draining lymph nodes and kidney allografts. Mechanistically, Tfr cell deletion increased GC B cell expression of pro-inflammatory cytokines such as IL-15. Neutralization of IL-15 compensated for the loss of Tfr cells and prolonged kidney transplant recipient survival. Together these data demonstrate the signals for Tfr cell development and how these cells restrain rejection by limiting alloreactive B cell responses. Overall design: Lymph node T follicular regulatory cells and Treg cells all in duplicate