IL-10-producing memory B regulatory cells as a novel target for HLA-G to prolong human kidney allograft survival

Despite the growing interest in the role of regulatory B cells (Bregs) in autoimmunity, their distinct role and function in kidney transplant outcomes remain elusive. Here, we retrospectively analyzed the proportion of Bregs, transitional Bregs (tBregs) and memory Bregs (mBregs) and their capacity to produce IL-10 in non-rejected (NR) versus rejected (RJ) kidney transplant recipients. In the NR group, we observed a significant increase in the proportion of mBregs (CD19⁺CD24^hiCD27⁺) but no difference in tBregs (CD19⁺CD24^hiCD38⁺), as compared to the RJ group. We also observed a significant increase in IL-10-producing mBregs (CD19⁺CD24^hiCD27⁺IL-10⁺) in the NR group. As our group and others have previously reported a potential role of the human leukocyte antigen G (HLA-G) in human renal allograft survival, notably through IL-10, we then investigated possible crosstalk between HLA-G and IL-10⁺ mBregs. Our ex vivo data suggest a role of HLA-G in enhancing IL-10⁺ mBreg expansion upon stimulation, which further decreased CD3⁺ T cell proliferation capability. Using RNA-sequencing (RNA-seq), we identified potential key signaling pathways involved in HLA-G-driven IL-10⁺ mBreg expansion, such as the MAPK, TNF and chemokine signaling pathways. Together, our study highlights a novel HLA-G-mediated IL-10-producing mBreg pathway that may serve as a therapeutic target to improve kidney allograft survival.