Donor selection determines the occurrence of acute graft-versus-host-disease(aGVHD)following allogeneic hematopoietic stem cell transplantation(allo-HSCT).To optimize the current clinical donor selection criteria and ...Donor selection determines the occurrence of acute graft-versus-host-disease(aGVHD)following allogeneic hematopoietic stem cell transplantation(allo-HSCT).To optimize the current clinical donor selection criteria and identify putative donor lymphocyte subsets associated with better recipient outcomes,we analyzed the peripheral CD4^(+)and CD8^(+)subsets in 80 granulocyte colonystimulating factor(G-CSF)mobilized donors and examined the aGVHD incidence of the corresponding 80 haploidentical and identical allo-HSCT recipients.The G-CSF-induced expansion of subsets varied among donors.We discovered a novel PD-1^(+)CD8^(+)CD45RA^(+)CCR7^(+)T lymphocyte subset in suitable donors that was significantly correlated with lower incidence of aGVHD and post-transplant anti-infection.The anti-aGVHD activity of this subset was confirmed in a validation cohort(n=30).Single-cell RNA sequencing revealed that this T cell subset exhibited transcriptomic features of stem cell-like memory T cell(TSCM)with both Treg and Teff activities which indicated its dual functions in aGVHD inhibition and graft-versus-leukemia(GVL)effect.Intriguingly,upon G-CSF mobilization,the donor PD-1^(+)CD8^(+)TSCM-like regulatory cells increased the PD-1 expression in a BCL6-dependent manner.Next,we showed that the mouse counterpart of this subset(PD-1^(+)CD8^(+)CD44^(-)CD62L^(+))ameliorated aGVHD,and confirmed the existence of this subset in clinical recipients.In summary,we,for the first time,identified a novel donor peripheral T cell subset suppressing aGVHD while promoting the immune reconstitution of recipients.It may serve as an indicator for optimal haploidentical and identical donor selection.Importantly,the dual Treg and Teff function of these T cells makes it a promising treatment for not only aGVHD but also auto-immune diseases.展开更多
基金supported by grants from the National Key Research and Development Program of China(2017YFA0104500)the Program for Scientific and Technological Innovation from the Science and Technology Commission of Shanghai Municipality(22490760400)+1 种基金the National Natural Science Foundation of China(Grant No.82071856,81671579,81930004)Key project at central government level:The ability establishment of sustainable use for valuable Chinese medicine resources(2060302).
文摘Donor selection determines the occurrence of acute graft-versus-host-disease(aGVHD)following allogeneic hematopoietic stem cell transplantation(allo-HSCT).To optimize the current clinical donor selection criteria and identify putative donor lymphocyte subsets associated with better recipient outcomes,we analyzed the peripheral CD4^(+)and CD8^(+)subsets in 80 granulocyte colonystimulating factor(G-CSF)mobilized donors and examined the aGVHD incidence of the corresponding 80 haploidentical and identical allo-HSCT recipients.The G-CSF-induced expansion of subsets varied among donors.We discovered a novel PD-1^(+)CD8^(+)CD45RA^(+)CCR7^(+)T lymphocyte subset in suitable donors that was significantly correlated with lower incidence of aGVHD and post-transplant anti-infection.The anti-aGVHD activity of this subset was confirmed in a validation cohort(n=30).Single-cell RNA sequencing revealed that this T cell subset exhibited transcriptomic features of stem cell-like memory T cell(TSCM)with both Treg and Teff activities which indicated its dual functions in aGVHD inhibition and graft-versus-leukemia(GVL)effect.Intriguingly,upon G-CSF mobilization,the donor PD-1^(+)CD8^(+)TSCM-like regulatory cells increased the PD-1 expression in a BCL6-dependent manner.Next,we showed that the mouse counterpart of this subset(PD-1^(+)CD8^(+)CD44^(-)CD62L^(+))ameliorated aGVHD,and confirmed the existence of this subset in clinical recipients.In summary,we,for the first time,identified a novel donor peripheral T cell subset suppressing aGVHD while promoting the immune reconstitution of recipients.It may serve as an indicator for optimal haploidentical and identical donor selection.Importantly,the dual Treg and Teff function of these T cells makes it a promising treatment for not only aGVHD but also auto-immune diseases.
