Increased Expression of Activating Receptors on NK Cells in the Post-Transplant Period.

Following allogeneic and autologous hematopoietic stem cell transplantation (HSCT) natural killer (NK) cells are among the first lymphocyte populations to recover, returning to normal levels within one month after HSCT. We previously reported that levels of IL-15, a cytokine critical to NK cell homeostasis, are elevated during the peri-transplant period (ASH, 2003). Modulation of the relative frequency and intensity of expression of the activating NK cell receptors by IL-15 may contribute to NK-mediated cytotoxicity post transplant. We compared the expression of activating NK receptors in the donor apheresis product and in recipient peripheral blood at one and three months following reduced intensity allogeneic HSCT from HLA-matched siblings. NK cells, divided into CD56^bright CD16⁻ and CD56^dimCD16⁺ subsets, were assessed for receptors that trigger cytotoxicity: the natural cytotoxicity receptors (NCR) NKp30 and NKp46, and the C-type lectin receptors NKG2D and NKG2C-CD94. During the first post transplant month the NK cell numbers recovered to normal levels, but the CD56^brightCD16⁻ subset increased disproportionately (p = .005). By three months the proportions of the NK cell subsets returned to pre-transplant levels. In both NK subsets, the percentage of cells expressing NCR NKp46 or NKp30 doubled by one month and was sustained at three months. The percentage of cells expressing the C-type lectin receptor CD94 similarly increased by 50% in both NK subsets. The heterodimeric activating partner of CD94, NKG2C, was also increased, but the increase in frequency of cells expressing this receptor was less than those pairing CD94 with its inhibitory NKG2A partner. The homodimeric activating receptor NKG2D increased in the NK CD56^brightCD16⁻ subset, but did not significantly change in the CD56^dim CD16⁺ NK population. Consistent with responsiveness to elevated IL-15 during the peri-transplant period, expression of both the IL-2/IL-15 beta and common gamma receptors increased at one and three months. Furthermore, when NK cells from normal donors were cultured with IL-15, we observed both a population shift towards CD56^brightCD16⁻ and an up-regulation of the NK cell activating receptors, similar to the changes observed during the early post transplant period. These results suggest that IL-15-dependent changes in NK subset distribution and activating NK receptor repertoire occur during the early post-transplant period. Up-regulation of activating NK cell receptors may contribute to NK cell anti-tumor efficacy in the post transplant period.