Donor programmed cell death 1 ligand 1 is required for organ transplant tolerance in major histocompatibility complex-mismatched mixed chimeras although programmed cell death 1 ligand 1 and major histocompatibility complex class II are not required for inducing chimerism

• Published in: American journal of transplantation Vol. 23; no. 8; pp. 1116 - 1129
• Main Authors: Huang, Yaxun, Wu, Xiwei, Tang, Shanshan, Wu, Huiqing, Nasri, Ubaydah, Qin, Qi, Song, Qingxiao, Wang, Bixin, Tao, Hansen, Chong, Anita S., Riggs, Arthur D., Zeng, Defu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2023
• Subjects: MHC II; mixed chimerism; organ transplant tolerance; PD-L1; NRP1; MHC II; LN; pTreg; MNC; mixed chimerism; Treg; MHC; HTX; SPL; DT; PB; organ transplant tolerance; MC; STX; PD-L1; HCT; HLA; COH; PD-1; Tem; WT; tTreg
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1016/j.ajt.2023.04.022

Induction of major histocompatibility complex (MHC) human leukocyte antigen (HLA)-mismatched mixed chimerism is a promising approach for organ transplantation tolerance; however, human leukocyte antigen-mismatched stable mixed chimerism has not been achieved in the clinic. Tolerogenic dendritic cell (DC) expression of MHC class II (MHC II) and programmed cell death 1 ligand 1 (PD-L1) is important for immune tolerance, but whether donor-MHC II or PD-L1 is required for the induction of stable MHC-mismatched mixed chimerism and transplant tolerance is unclear. Here, we show that a clinically applicable radiation-free regimen can establish stable MHC-mismatched mixed chimerism and organ transplant tolerance in murine models. Induction of MHC-mismatched mixed chimerism does not require donor cell expression of MHC II or PD-L1, but donor-type organ transplant tolerance in the mixed chimeras (MC) requires the donor hematopoietic cells and the organ transplants to express PD-L1. The PD-L1 expressed by donor hematopoietic cells and the programmed cell death 1 expressed by host cells augment host-type donor-reactive CD4+ and CD8+ T cell anergy/exhaustion and differentiation into peripheral regulatory T (pTreg) cells in association with the organ transplant tolerance in the MC. Conversely, host-type Treg cells augment the expansion of donor-type tolerogenic CD8+ DCs that express PD-L1. These results indicate that PD-L1 expressed by donor-type tolerogenic DCs and expansion of host-type pTreg cells in MHC-mismatched MCs play critical roles in mediating organ transplant tolerance.