Natural killer (NK) cells are crucial albeit dichotomous players in solid organ transplantation, as they have recently been shown to be critical contributors to both allograft rejection and tolerance induction. Our previous studies show that this dichotomous role can be explained by differences in NK cells’ cytokine-dependent activation status, as NK cells, once preactivated by IL-15, become potent effector cells in acute allograft rejection. Going one step further, we now have new data demonstrating that NK cells are functionally heterogeneous and that distinct NK cell subsets respond differently to cytokine-mediated activation. Based on this we speculate that NK cells can be classified into pro-tolerant and pro-inflammatory NK cell subsets according to “high” and “low” responsiveness to cytokine-dependent activation, and are seeking this funding to test this hypothesis and gain further understanding of the role distinct NK cell subsets play in transplant tolerance and rejection. Since the role of NK cells as effector cells in transplantation has not been adequately addressed, especially in the early phase posttransplantation, and therapeutic strategies to modulate NK cells are currently lacking, our work may have an important impact on the development of new clinical tolerance induction protocols.
