Beyond licensing and disarming: A quantitative view on NK‐cell education

Abstract

In this article, we will move beyond the current controversy of different models for NK‐cell education and instead discuss the properties characterizing MHC class I‐guided functional development of NK cells. We will argue that this development, which represents the endpoint of NK‐cell education, is a quantitative and dynamic, and perhaps even reversible, process.

When NK cells overcome their lack of education

“…When NK cells cannot sense self MHC-I, as in MHC-I-deficient mice or patients, individuals do not develop autoimmune disorders, and the NK cells are hyporesponsive to stimulation in vitro ( Figure 1A) (6)(7)(8). Various conflicting models have been proposed to describe how the interaction of MHC-Ispecific receptors with their ligands contributes to NK cell education (2)(3)(4)(5). A unifying model inspired from the arming/ disarming model initially proposed by David Raulet and colleagues (2) is consistent with the experimental data published so far.…”

“…The functional maturation of NK cells includes a process of education, also referred as to licensing, arming, or tuning, by which NK cells acquire effector functions that are adapted to the host in which they develop (2)(3)(4)(5). In addition to its wellknown role in the regulation of NK cell effector functions, MHC-I recognition by inhibitory receptors is also involved in NK cell education.…”

“…In this issue, Nagashimada et al (4), in a truly remarkable study, have now provided a real insight into how a mutation in PHOX2B, a gene that encodes a paired homeodomain transcription factor that plays a critical role in the development of crest-derived autonomic neurons (5), can act in different cells in a gain-of-function or in a loss-of function manner. The gainof-function activity is tumorigenic, causing neuroblastomas (NBs) to arise in the sympathetic nervous system, while perversely synergizing with the loss-of-function effect to disrupt neurogenesis, sympathetic gangliogenesis, and crest cell colonization of the terminal bowel, which becomes aganglionic (Hirschsprung disease [HSCR]).…”

Mechanisms of NK cell activation: CD4+ T cells enter the scene

“…Many reviews have covered this topic, which will therefore not be discussed in detail here [88][89][90][91][92]. Briefly, NK cells are hyporesponsive when they cannot recognize self-MHC class I molecules via their inhibitory receptors.…”

Inhibitory Killer Immunoglobulin-like receptors to self HLA-B and HLA-C ligands contribute differentially to Natural Killer cell functional potential in HIV infected slow progressors

“…The rheostat model of NK licensing postulates that NK cell education is a quantitative and dynamic process whereby the strength of the signals delivered by iKIR following engagement with MHC class I molecules is proportional to a threshold of activation that is set in the NK cells [5]. Different degrees of inhibitory and activating receptor input quantitatively tune the activation pathways of the NK cell and translate into corresponding levels of responsiveness [6;11;23;24].…”