Natural killer cell regulation - beyond the receptors

Abstract

Natural killer (NK) cells are lymphocytes that are important for early and effective immune responses against infections and cancer. In the last 40 years, many receptors, their corresponding ligands and signaling pathways that regulate NK cell functions have been identified. However, we now know that additional processes, such as NK cell education, differentiation and also the formation of NK cell memory, have a great impact on the reactivity of these cells. Here, we summarize the current knowledge about these modulatory processes.

Figure 1.. NK cell education: adaption of the responsiveness depending on inhibitory receptor - ligand interactions

(a) In normal major histocompatibility complex (MHC) class I-sufficient individuals (humans and mice), NK cells expressing inhibitory receptors recognizing those MHC class I molecules become educated. Those cells are responsive to activating receptor stimulation. The subset of NK cells that lacks inhibitory receptors for self MHC class I are non-educated and hyporesponsive when triggered through activating receptor stimulation. Under certain conditions, such as infections or cytokine stimulation, this subset can become responsive. (b) In MHC class I-deficient individuals, NK cells are non-educated and hyporesponsive due to the lack of inhibitory ligands. After transfer to a new MHC class I-sufficient host, NK cells can become “re-educated” and responsive if they express the matching inhibitory receptors. KIR, killer cell immunoglobulin-like receptor.

Figure 2.. Adaption of NK cell reactivity during differentiation

Functionally distinct subsets of human NK cells differ in their surface receptor expression and their reactivity towards activating receptors triggering or cytokine stimulation. See text for details. IFN, interferon; IL, interleukin; KIR, killer cell immunoglobulin-like receptor.