Quantity and Quality Reconstitution of NKG2A Natural Killer Cells Are Associated with Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation.

The immune mechanism underlying graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (HSCT) remains unclear. Natural killer (NK) cells play a crucial role in mediating pathogen-specific immunity and are the first donor-derived lymphocytes reconstituted post-HSCT. However, NK cells vary at different stages after HSCT. Here, we found that the absolute NKG2A subset cell counts and the percentages of NKG2A among NK cells were significantly reduced in GVHD patients after HSCT compared with those from non-GVHD patients. Moreover, the reduction in NKG2A NK cells in post-HSCT GVHD patients was ascribed to increased apoptosis and a decreased proliferation capacity while retaining a strong graft-versus-leukemia effect. In vitro assays showed that co-culture of T cells with NKG2A NK cells significantly reduced IFN-γ secretion by T cells and increased IL-4 secretion. Moreover, the CD25 expression level was decreased, whereas the number of cells with the CD4CD25FOXP3 phenotype was increased. In addition, the NKG2A NK cells induced T cell apoptosis and decreased T cell proliferation during the co-culture process. Importantly, NKG2A NK cells mainly regulated activated but not resting T cells. In vivo assays showed that the serologic IL-10 level was evidently lower in GVHD than in non-GVHD patients, whereas the IL-1β, IFN-γ, and tumor necrosis factor-α levels were higher in GVHD patients. Furthermore, the NKG2A NK cell ratio from GVHD patients was markedly increased by the presence of exogenous IL-10 but not by other cytokines. In contrast, the NKG2A cell ratio from non-GVHD patients was not increased by IL-10. Therefore, post-HSCT GVHD may be ascribed to the reduced induction of NKG2A NK cells by IL-10, which further overactivates T cells.