The proinflammatory cytokines IL-2, IL-15 and IL-21 modulate the repertoire of mature human natural killer cell receptors

Natural killer (NK) cells are an important population of lymphocytes that originally were regarded to play crucial roles in protection from infectious disease and destroying tumour cells; they are also involved in certain autoimmune diseases and in rejection of transplanted tissues [1,2]. NK cells express many different germline encoded activating or inhibitory receptors that do not rearrange, in contrast to T and B cells, which might suggest that NK cells are unable to respond to more than a limited number of stimuli [3]. The human NK receptors are characterized by genetic diversity, and NK cells were found to express only a subset of these receptors [4,5]. NK cells can be divided into CD56bright and CD56dim subpopulations, the former being more inclined to produce cytokines such as IFN-γ and the latter to lyse target cells [6]. Several activating and inhibitory NK cell receptors have been well characterized, of which killer cell immunoglobulin-like receptors (KIRs), c-type lectins, and natural cytotoxicity receptors (NCRs). Although inhibitory receptors neutralize NK cells, activating receptors are responsible for NK cell activity [3,7-9]. The NK repertoire and its modulation at the cell surface is incompletely understood. Many of the activating receptors are constitutively expressed on all NK cells, and it is actually the increased expression of their ligands on other cells induced by mild stimuli that underpins the diversity of activating receptors.The genetic diversity of NK cell receptors and the range of diseases in which they are thought to play specific roles would suggest that they might potentially be good therapeutic targets. To date, the suitability of KIR as a target of intervention has been suggested by studies of bone marrow transplantation [10-12]. Exploitation of NK alloreactivity may become an important therapeutic strategy in the management of myeloid malignancy, in the modulation of engraftment procedures and in the control of graft-versus-host-