**7. The effects of natural killer cells on graft-versus-host disease**

Allo-HSCT has curative potential through donor immune effectors-mediated GvL effects. However, the donor versus host direction effect of alloreactive T cells also causes GvHD which is a major complication of allo-HSCT [2]. Depletion of donor T cells in grafts and application of immunosuppressive pretreatment are often used to eliminate GvHD; however, these treatments also hampers GvL effects at the same time. NK cells have also been shown to play an important role in GvHD. In murine models, alloreactive NK cells are shown to kill antigen presenting cells (APCs) thereby prevent the initiation of aGvHD [100]. Correspondingly, another study demonstrated that alloreactive NK cells can be recruited into the lymph nodes and suppress T cells activation through cytotoxicity toward allogeneic dentritic cells (DCs) [149]. Donor NK cells may also mediate suppression of aGvHD through the direct killing of activated donor alloreactive T cells [150]. The possible mechanism involves the interactions between activating receptor NKG2D and its ligand highly expressed on the surface of activated T cells, which help NK cells to discriminate activated T cells from normal T cells and initiate killing [151, 152]. NK cells were also found to inhibit aGvHD through cytokine production such as TGF-β [153]. Furthermore, NK cells were able to inhibit the proliferation of donor CD4<sup>+</sup> T cells and reduce the risk of cGvHD [154]. Remarkably, donor NK cells are believed not to attack normal host tissues mainly due to the absence of activating receptor ligands on normal nonhematopoietic cells [155].

Although these previous experimental studies suggested that donor NK cells may have potential role in modulating GvHD, the clinical results are variable. Ruggeri L et al. reported NK cell alloreactivity was favorably associated with the lower risk of aGvHD [6]. However, this benefit effect cannot be observed in most groups, some groups even found KIR mismatch may worsen GvHD [156, 157]. Notably, in a recent clinical trial, IL-15/4-1BBL-activated donor NK cell infusion was found to contribute to aGvHD in T-cell depleted HSCT [158]. Collectively, these contradictory results indicated the role of alloreactive NK cells in GvHD may be variable. They could either aggravate or attenuate GvHD probably depended on different immune microenvironment in HSCT. Correspondingly, in our study of murine acute GvHD model, IL-12/15/18-preactivated donor NK cells significantly inhibited severe aGvHD, whereas they accelerated the development of aGvHD in a mild aGvHD model (unpublished data).
