Abstract
Objectives: The mechanism and immunoregulatory role of human natural killer (NK) cells in acute graft-vs.-host-disease (aGVHD) remains unclear. This study quantitatively analyzed the cytotoxicity of donor NK cells toward allo-reactive T cells, and investigated their relationship with acute GVHD (aGVHD).Methods: We evaluated NK dose, subgroup, and receptor expression in allografts from 98 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). A CD107a degranulating assay was used as a quantitative detection method for the cytotoxic function of donor NK cells to allo-reactive T cells. In antibody-blocking assay, NK cells were pre-treated with anti-DNAM-1(CD226), anti-NKG2D, anti-NKP46, or anti-NKG-2A monoclonal antibodies (mAbs) before the degranulating assay.Results: NK cells in allografts effectively inhibited auto-T cell proliferation following alloantigen stimulation, selectively killing alloantigen activated T cells. NKG2A− NK cell subgroups showed higher levels of CD107a degranulation toward activated T cells, when compared with NKG2A− subgroups. Blocking NKG2D or CD226 (DNAM-1) led to significant reductions in degranulation, whereas NKG2A block resulted in increased NK degranulation. Donor NK cells in the aGVHD group expressed lower levels of NKG2D and CD226, higher levels of NKG2A, and showed higher CD107a degranulation levels when compared with NK cells in the non-aGVHD group. Using univariate analysis, higher NK degranulation activities in allografts (CD107ahigh) were correlated with a decreased risk in grade I–IV aGVHD (hazard risk [HR] = 0.294; P < 0.0001), grade III–IV aGVHD (HR = 0.102; P < 0.0001), and relapse (HR = 0.157; P = 0.015), and improved overall survival (HR = 0.355; P = 0.028) after allo-HSCT. Multivariate analyses showed that higher NK degranulation activities (CD107ahigh) in allografts were independent risk factors for grades, I–IV aGVHD (HR = 0.357; P = 0.002), and grades III–IV aGVHD (HR = 0.13; P = 0.009).Conclusions: These findings reveal that the degranulation activity of NK in allografts toward allo-activated T cells was associated with the occurrence and the severity of aGVHD, after allogeneic stem cell transplantation. This suggested that cytotoxicity of donor NK cells to allo-reactive T cells have important roles in aGVHD regulation.
Highlights
Natural killer (NK) cells are the first donor-derived subset of lymphocytes that are reconstructed following allogeneic hematopoietic stem cell transplantation
We investigated the role of NK cells in the regulation of T cell allo-reactivity in human allo-HSCT, and demonstrated that cytotoxicity of donor NK cells toward alloreactive T cells was associated with the occurrence of overall and grade III–IV acute graft-vs.-host-disease (aGVHD)
No significant differences were observed in patient age, patient sex, gender matching between donors and recipients, underlying disease, donor source, conditioning regimen, serotherapy, killer immunoglobulinlike receptor (KIR)-L mismatch, and dose of CD34+, CD3+, or CD56+ cells in allografts between the GVHD group and the non-aGVHD group
Summary
Natural killer (NK) cells are the first donor-derived subset of lymphocytes that are reconstructed following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Some studies have demonstrated that killer immunoglobulinlike receptor (KIR)-ligand mismatches trigger donor vs recipient NK cell allo-reactivity, suppressing the development of aGVHD by ablating host antigen-presenting cells (APCs), which are essential for the activation of donor T cell in aGVHD [5,6,7]. Studies have demonstrated that activated T cells up-regulate the expression of ligands for activating NK cell receptors, making them vulnerable to NK cell killing though the “induced-self ” model [25, 26]. As donor NK and T cells share similar trafficking routes after allo-HSCT [27], and recent studies have shown that NK cells exert cytotoxicity toward activated T cells [28, 29], the NK cell–mediated direct lysis of allo-reactive T cells through the “induced-self ” model may present an important mechanism for aGVHD regulation by NK cells. We know little about the role of NK cell cytotoxicity toward allo-reactive T cells in human aGVHD
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