**4. Donor natural killer cell reconstitution after hematopoietic stem cell transplantation**

NK cells need to develop *in vivo* to acquire effector function following HSCT. Accordingly, they are the first donor-derived lymphogenous cells to reconstitute and can be detected as early as the first month post-transplant [90]. The reconstitution kinetics and functional properties of NK cells are variable due to the primary activity of NK cells in the graft and different graft source including bone marrow, G-CSF-mobilized peripheral blood stem cell, and UCB. Series studies demonstrated that different grant source did not affect the rate of NK cell reconstitution and during the early stage post-HSCT, the primary NK cell subsets were CD56bright donor NK cells [91, 92]. These results indicated that the early reconstituting NK cells after HSCT were mainly generated from the differentiation and maturation of NK precursors but not the expansion of mature NK cells in the graft. Nevertheless, the expansion of adoptive transferred NK cells also influences the reconstitution of donor NK cells since Eissens et al. find that in HLA-matched allogeneic peripheral blood stem cell transplantation, CD3<sup>+</sup> /CD19<sup>+</sup> -depleted grafts which contain more mature NK cells than CD34<sup>+</sup> -selected grafts lead to more rapid NK cell reconstitution [93].

Although donor-derived NK cells are observed very early post-HSCT, they have an immature CD56bright KIR− NKG2A<sup>+</sup> phenotype for at least 3-6 months [94]. Interestingly, the ability of these immature CD56bright NK cells to produce IFN-γ is significantly impaired in response to tumor cell line or primary leukemia cells [95, 96]. The expression of T-bet and mucin-containing domain-3 (Tim-3) is much lower in the patients post-HSCT compared with the healthy individuals [97]. Both of these two molecules are critical for induction of IFN-γ production, thus their reduced expression may partly account for the decreased recovery of cytokine production.

It is difficult to clearly define the effect of T cell content in the graft on NK cell reconstitution as it is also depended on immunosuppressive therapy. By far, graft T cell content is thought to significantly influence functional reconstitution of NK cells rather than numerical reconstitution. One study observed donor-derived NK cells reconstitution following HSCT with three different kinds of donor source including T-cell-replete adult grafts, T-cell-deplete adult grafts, and UCB [95]. Both of the T-cell-replete group and UCB group were treated with immunosuppression. They found KIR expression in T-cell-replete group was the highest among these three groups indicated donor-derived NK cells in this group may have better effector function. Accordingly, in an earlier study by the same group, they found IFN-γ production was more potent following HSCT with T-cell-replete grafts compared to T-cell-deplete transplantation [98]. These results were consistent with the observations by Nguyen et al. which demonstrated that without immunosuppression, recovery NK cells in the partial T-cell-depleted group had lower cytotoxicity than NK cells in the full T-cell-depleted group [92]. In summary, graft T cell content trends to enhance functional reconstitution of NK cells irrespective of immunosuppression. This promotion effect may be due to activation from T-cell-derived IL-2, or stimulation from other inflammatory cytokine such as IL-12 and IL-18, which are increased following donor T cell engraftment. Finally, CMV infection and GvHD may also have potent effect on NK cell reconstitution, and we will discuss this in the following sections.
