It takes a village.

The education of natural killer (NK) cells is a process by which the engagement of NK cell receptors by their ligands modifies subsequent NK cell responses through other receptors, in particular when target cells lack ligands for the educating receptors1–3. Paradoxically, education by inhibitory receptors enhances future activation responses, whereas education by activating receptors suppresses subsequent activation responses. Despite such understanding, little is known of the intracellular pathways and mechanisms that mediate NK cell education. In this issue of Nature Immunology, Jelenčić et al.4 report that engagement of the activating receptor NKG2D on immature NK cells modifies subsequent NK cell responses by another activating receptor, NCR1 (NKp46)5–7. More notably, they also outline the molecular mechanism responsible for this effect. This elegant study provides new insights into how education occurs at the molecular level, with potential broad applicability to other educating receptors. The education of NK cells has been variably called ‘licensing’, ‘arming’, ‘disarming’, ‘sensitization’, ‘desensitization’ and ‘tuning’1–3. Ever since this phenomenon was identified, much interest has been directed at understanding its molecular basis. In particularly, one has to wonder how the engagement of an inhibitory receptor promotes the subsequent activation of NK cells and vice versa. The most-studied educating receptors are the inhibitory receptors of the Ly49 and KIR families. These receptors recognize as ligands major histocompatibility complex class I molecules, which are ubiquitously expressed on normal cells. Engagement of inhibitory Ly49 receptors or KIRs by their ligands, either during NK cell development or after NK cell development, promotes the ability of NK cells to respond to target cells deficient in major histocompatibility complex class I. In adoptive-transfer experiments, it was observed that this effect is reversible. An analogous process was subsequently documented for other inhibitory receptors, including SLAMF6 and TIGIT8,9. Much of the evidence suggests that for inhibitory receptors, education is mediated by the tyrosine phosphatase SHP-11–3,10. SHP-1 can directly bind to the cytoplasmic domain of inhibitory Ly49 receptors, KIRs and SLAMF6 and can dephosphorylate several proteins involved in the activation of NK cells. However, the relevant substrates of SHP-1 that lead to education have remained unidentified. Moreover, how regulation of these substrates would enhance subsequent NK cell responses is unclear. Along these lines, it has been reported that education by inhibitory Ly49 receptors is accompanied by a redistribution of activating receptors at the plasma membrane11, while education by SLAMF6 results in augmented activation of the Src family of tyrosine kinases after triggering of activating NK cell receptors9. Kinases of the Src family have a key role in initiating the activation of NK cells in response to most, if not all, activating NK cell receptors. On the basis of those two studies9,11, it has been hypothesized that NK cell education might result from physical or functional reorganization of the signaling machinery linked to the activation of NK cells. In their study, Jelenčić et al. observe that the activating receptor NKG2D, which recognizes ligands on stressed cells, inhibits future responses through another activating receptor, NCR1, which recognizes mainly unknown ligands4. More specifically, they find that NKG2D-deficient mice display an increased ability to eliminate tumor cells and control infections through NCR1. Analyses of mice with conditional deletion of NKG2D, in which NKG2D expression is eliminated after expression of NCR1, provides an indication that NKG2D mediates this effect in immature NK cells, before expression of NCR1 is acquired. Thus, unlike the effect of other educating receptors1–3, the effect of NKG2D on the function of NCR1 persists even when expression of NKG2D is lost, which suggests that this is not reversible. However, one Hematopoietic cell