Fig. 1

NK cell education and activation pathways. NK cell education can be mediated by iKIRs (KIR2DL1) as well as aKIRs (KIR2DS1) expressed at the immature NK cell membrane. In case of education by iKIR (a), a bond between iKIR and self-HLA is necessary to develop fully functional NK cells, whereas its absence abrogates NK cell education resulting in hypo-responsive NK cells. In contrast, in aKIR mediated education (b) is the absence of the aKIR-ligand necessary for the licensing of immature NK cells, whereas its presence will generate hypo-responsive NK cells. KIR/HLA interactions also play a pivotal role in the activation of NK cells (c). Tolerance (red minus) can be mediated by the presence of an inhibitory receptor (Inh-R) -HLA bond and the absence of an activating impulse (red minus) (c.1.) or solely by the absence of an activating signal (c.2). However in the absence of the Inh-R-ligand bond (“missing self”) an activating NK cell receptor (Act-R) binding non-HLA class I ligands (Act-L) (“induced self”) suffices to induce a cytotoxic NK cell response (green plus) (c.3). NK cell activation is also provoked in the presence of viral/tumor peptides in the HLA class I binding groove of target cells, benefitting the HLA class I-binding affinity of aKIRs (“altered self”) at the expense of iKIRs (“missing self”) (green plus) (c.4)