Natural killer cells in autoimmunity: clues or tools?

Natural killer (NK) cells are large granular lymphocytes involved in clearance of damaged cells such as neoplastic and virus infected cells. Despite usual classification, NK cells are now grouped among the so called immune lymphoid cells (ILCs) which play fundamental roles in innate immunity and also in tissue remodeling. As other ILCs, NK cells are characterized by a wide spectrum of functions and participate in various phases of immune system activation or suppression by producing large amounts of soluble mediators. They are classically involved in cytotoxic responses even if they can regulate other immune cells by cell-cell interactions and can also generate memory subsets linking them to adaptive immunity. In spite of the intrinsic difficulties to investigate NK cells role in autoimmune diseases, data increasingly suggests that these lymphocytes could operate in self-tolerance breakdown but also in the control of autoimmune reactions playing a double role. In fact, NK cells can directly down regulate autoimmune responses by acting on immune cells or by diminishing the exposition of auto-antigens even if, they can enhance a pathological state of autoimmunity stimulating both natural and adaptive immune compartments. This review is focused on recent findings on NK cell biology, classification, activation, trafficking and organ distribution but also on interactions with other immune cells. It will explore their tasks in autoimmunity ranging from connective tissue diseases to allergic conditions with particular attention on the most recent studies. It will discuss NK cells putative role in breakdown or self-tolerance maintenance and the possibility to manipulate them for treatment purposes.