Development of natural killer cell diversity

Natural killer (NK) cells were discovered some 30 years ago due to their capacity to spontaneously lyse tumour target cells in vitro. Although initially received with scepticism, the 'natural' cytotoxicity exhibited by NK cells has been molecularly dissected and is now generally accepted as an alternative cellular mechanism to detect infected, stressed or transformed cells. Subsequent studies showed that during viral or bacterial infections, NK cells are also prodigious cytokine producers, and by their ability to rapidly amplify and recruit inflammatory cells they play an important role in innate immunity. Thus, in a short period of time, NK cells have evolved from a 'tissue culture artefact' to an essential player in the innate immune defence system. Most immunologists view NK cells as rapidly-reacting innate lymphocytes that perform stereotyped roles including target cell lysis and IFN-γ secretion to promote Th1 responses. Nevertheless, several reports suggest that NK cells exhibit functional diversity that may be subserved through distinct NK cell subsets. In addition to the bone marrow, multiple tissue sites (including the thymus, lymph node and intestine) can generate cells bearing NK-specific markers that show distinct functional properties. In some cases (for example, at mucosal surfaces), NKp46+ cells play an important role in tissue homeostasis through a cross-talk with epithelial cells. In this situation, these 'NK' cells are clearly distinguished from classical NK cells that are involved in immune defence. These recent observations suggest that NK cells should be considered not only in 'reactive' innate immunity both also in 'pre-emptive' defence that operates by improving barrier functions at epithelial surfaces.