Alloreactive natural killer cells promote haploidentical hematopoietic stem cell transplantation by expansion of recipient-derived CD4(+) CD25(+) regulatory T cells.
Alloreactive NK cells (Allo-NKs) have been shown to exert advantageous effects on the outcomes of haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) for cancer treatment. However, the mechanisms of action of Allo-NKs remain unclear. We established a novel Haplo-HSCT conditioning regimen composed of Allo-NKs and a low dose of immunosuppressive drugs (Allo-NKs + Chemo) to investigate alternative mechanisms besides direct cytotoxicity. The inhibitory effects of different cell subsets on the donor-recipient mixed lymphocyte reactions (MLRs) were evaluated after Haplo-HSCT. The quantities and functions of CD4(+) CD25(+) regulatory T cells (Tregs) and dendritic cells (DCs) in the spleen and the thymus were examined. Our results showed that the Allo-NKs + Chemo regimen induced systemic tolerance, and that CD4(+) CD25(+) Tregs played a significant role in inducing and maintaining systemic tolerance after Haplo-HSCT. Alloreactive NK cells promoted the expansion of recipient-derived CD4(+) CD25(+) CD127(-) Tregs in the thymus and the spleen which could be amplified in vitro by the immature donor-derived DC subset isolated from the thymus of Allo-NKs + Chemo-treated mice. Our findings suggested that Allo-NKs are capable of inducing systemic tolerance after Haplo-HSCT by assembling donor-derived immature DCs to expand recipient-derived Treg cells in the thymus.
Department of Immunology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Jinpu
J
Yu
Xiubao
X
Ren
Fang
F
Yan
Hui
H
Li
Shui
S
Cao
Yan
Y
Chen
Haiyan
H
Sun
Xiumei
X
An
Naining
N
Zhang
Xishan
X
Hao
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003520:Cyclophosphamide / Q000627:therapeutic use; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007694:Killer Cells, Natural; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology; D019172:Transplantation Conditioning; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
D053645:Interleukin-2 Receptor alpha Subunit; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine