DNAM-1: would the real natural killer cell please stand up!

Natural Killer (NK) cells were called as such due to their ability to spontaneously kill tumor cell lines in vitro. Peripheral NK cells have long been considered rapid responding innate effector lymphocyte primed to produce cytotoxic granules and pro-inflammatory cytokines such as IFN-γ and TNF-α when they encounter virusinfected, transformed or damaged self-tissue. However, it is becoming clear that considerable heterogeneity exists with the peripheral NK cell pool and researchers should reconsider the generalized view of NK cell effector function and contribution to mammalian immunity. This is extremely relevant to tissues such as the liver, salivary gland and intestine where type 1 innate lymphoid cells (ILC1) are found and resemble NK cells in many regards yet have distinct transcription factor requirements to conventional NK cells. For over 10 years now we have known that NK cells of various maturational stages can be found in tissues such as the spleen, lymph nodes, liver and lung and these NK cells exhibit differential responsiveness to homeostatic cytokines and effector responses. These differential responses were attributed to the alternate maturation state however a recent report from Martinet et al. has revealed that functional heterogeneity exists amongst NK cells of similar maturation based on DNAM1 expression [1]. DNAM-1 (CD226) is a cell surface glycoprotein that functions as an adhesion molecule to synergize with activating receptors and trigger NK cellmediated cytotoxicity upon interaction with its ligands CD155 and CD112 [2]. The authors found that DNAM-1 expression is unanimous on NK cell progenitors, however is down-regulated as NK cells mature, generating DNAM1+ and DNAM-1NK cells in the periphery. The ratio of DNAM-1+ NK cells to DNAM-1NK cells diminishes from birth and the DNAM-1subset does not appear to revert to a DNAM-1+ state. DNAM-1 expression did not correlate with other known markers of NK cell maturation such as KLRG1 [3] and CD27/CD11b [4] with both KLRG1+ and CD27/CD11b NK cell subsets expressing similar proportions of DNAM-1+ and DNAM-1NK cells. Instead, DNAM-1 expression was strongly linked to NK cell effector functions with DNAM-1+ NK cells producing Editorial