Monica Killig

During the early phase of an inflammatory response, innate cells can use different strategies to sense environmental danger. These include the direct interaction of specific activating receptors (actR) with pathogen-encoded/danger molecules or the engagement of cytokine receptors by pro-inflammatory mediators produced by antigen presenting cells (APC) in the course of the infection. These general recognition strategies, which have been extensively described for innate myeloid cells, are shared by innate lymphoid cells (ILC), such as Natural Killer (NK) cells. The family of ILC has recently expanded with the discovery of group 2 (ILC2) and group 3 ILC (ILC3), which play an important role in the defense against extracellular pathogens. Although ILC3 and NK cells share some phenotypic characteristics, the recognition strategies employed by the various ILC3 subsets have been only partially characterized. In this review, we will describe and comparatively discuss how ILC3 sense environmental cues and how the triggering of different receptors may regulate their functional behavior during an immune response.

Natural killer (NK) cells are part of the innate lymphoid cell (ILC) family and represent the main cytotoxic population. NK cells develop from bone marrow common lymphoid progenitors and undergo terminal differentiation in the periphery, where they finally gain their cytotoxic competence as well as the ability to produce IFN-gamma in response to engagement of activating receptors. This process has been at least partially elucidated and several markers have been identified to discriminate different NK cell stages and other ILC populations. NK cell terminal differentiation is not only associated with progressive phenotypic changes but also with defined effector signatures. In this essay, we will describe the phenotypic and functional characteristics of the main stages of NK cell development and terminal differentiation and discuss them in light of recent discoveries of novel ILC populations.

NK-cell tolerance to self is mediated via engagement of inhibitory receptors by cognate MHC molecules. This event is critical for NK-cell education to achieve functional competence. Thus, NK cells expressing self-MHC-specific inhibitory receptors are responsive to activating stimuli while those lacking such receptors are hyporesponsive. Nevertheless, the mechanisms underlying NK-cell education are still poorly understood. Here, we show that after stimulation with cytokines, hyporesponsive NK cells acquire stable expression of killer Ig-like receptors (KIR) as reflected by DNA hypomethylation of their KIR locus. Remarkably, only hyporesponsive NK cells that acquire KIR in the presence of their cognate MHC molecule gain functional competence and this process can occur in the absence of any accessory cells. Acquisition of competence does not result in autoreactivity, since acquired KIR are functional and therefore able to inhibit NK-cell cytotoxicity. Our data demonstrate that competent NK cells can be generated by cytokine stimulation, suggesting that NK-cell education might not only be an early event which takes place during NK-cell development but might also occur in the periphery during an immune response.