Natural Killer Cell Education and the Response to Infection and Cancer Therapy: Stay Tuned

Abstract

The functional capacities of natural killer (NK) cells differ within and between individuals, reflecting considerable genetic variation. 'Licensing/arming', 'disarming', and 'tuning' are models that have been proposed to explain how interactions between MHC class I molecules and their cognate inhibitory receptors - Ly49 in mice and KIR in humans - 'educate' NK cells for variable reactivity and sensitivity to inhibition. In this review we discuss recent progress toward understanding the genetic, epigenetic, and molecular features that titrate NK effector function and inhibition, and the impact of variable NK cell education on human health and disease.

Figure 1. NK cell education and functional outcomes of NK:target interactions

(A) NK cells express variable combinations of inhibitory receptors. Only some NK cells will display inhibitory receptors capable of binding co-inherited MHC class I molecules. Cells bearing inhibitory Ly49 or KIR molecules for self MHC class I molecules are educated and exhibit the lowest threshold for activation. NK cells that do not express inhibitory receptors for self-MHC class I molecules are “uneducated” and require higher activation signals (+) to become reactive, but are insensitive to inhibition (−) by self-MHC class I. Hence, education programs a different reactive threshold to each NK cell; shown are relative requirements for activating signals in representative educated and uneducated NK cells. (B) against an HLA-negative target cell expressing an activating ligand, educated NK cells are activated but as uneducated NK cells exhibit a higher threshold for reactivity, they are hyporesponsive against the same target. (C) Against an HLA-positive target cell, activation is nullified by inhibitory signaling through KIR and the educated NK cell is hyporesponsive. Uneducated NK cells are refractory to inhibition because they lack cognate inhibitory receptors for “self” class I molecules, but also require a high signal for activation. Without strong stimulation, uneducated NK cells are hyporesponsive to target cells. (D) Accessory activating factors, including pro-inflammatory cytokines (not shown) or antibodies, which trigger NK cells for ADCC, support activation of both educated and uneducated NK cells.

Figure 2. Molecular features of NK cell education

NK cell education increases with a cell’s sensitivity to inhibition by “self” class I molecules and can be additive based on the co-expression of multiple receptor types. Shown is a schematic heatmap describing the relative expression and function of NK cells with increasing education from left to right. Potential receptor expression profiles associated with increasing education are presented at the top of the table (black boxes indicates expression). Factors are shown on a yellow (low) to red (high) heatmap and striped cells indicate factors that are not uniformly expressed on a population of cells or consistently changed with increasing activation. Where cells are white, data are not available. *DNAM-1 is required for the expansion of adaptive NK cells, but downregulated after their differentiation. **CD57 is expressed on a fraction of cells; this proportion increases with education.

Figure 3. Models of NK education

Natural killer cells stochastically express activating and inhibitory receptors. The quantity of inhibitory input triggered by “self” MHC in each NK cell programs its education. Three models exist to describe the process of education. (A) The licensing/arming model postulates that developing NK cells capable of binding self-MHC class I molecules are endowed with higher effector potential, while those that cannot bind self-MHC class I molecules will be programmed for lower reactivity. (B) The disarming model postulates that all developing NK cells are initially capable of high effector responses, but only those that are capable of inhibition by self-MHC binding can rescue themselves from activation-induced anergy. As a result, those NK cells which are sensitive to “self” class I remain highly reactive, while those that cannot bind “self” class I lose effector potential, becoming comparatively hyporesponsive. (C) The rheostat model postulates that the avidity of the total interactions between inhibitory receptors and class I molecules tunes the reactivity of each NK cell. Those with fewer interactions with self-MHC class I binding exhibit the lowest effector potential, while those with intermediate and high numbers of interactions with self-MHC molecules exhibit intermediate and strong reactivity, respectively. (D) All three models are compatible with “tuning”, wherein the reactivity of an NK cell can be adjusted up or down in response to changes in the local environment.

Figure 4. Graded education by allelic variation: the example of KIR3DL1 and HLA-B

KIR3DL1 is expressed as null (n), low (l) and high (h) -density alleles. Subsets of HLA-B exhibiting the Bw4 epitope act as ligands for KIR3DL1, with expression density and binding affinity correlating to the amino acid present at position 80: threonine (80T) or isoleucine (80I). Subtype combinations of KIR3DL1 and HLA-B generate a spectrum of reactive and inhibitory potentials among NK cells. Shown are the educating outcomes of various combinations of KIR3DL1 and HLA-B alleles. HLA-B molecules lacking the Bw4 epitope (Bw6) do not educate NK cells through any KIR3DL1 receptor. Both the Bw4-80I and -80T subtypes educate NK cells, with the highest education observed among subtype combinations of KIR3DL1-h and HLA-Bw4-80I. Intermediate education is conveyed by all other combinations of Bw4 and KIR3DL1, including the KIR3DL1-n subtype which is retained intracellularly but nevertheless conveys education to the NK cell. The intracellular retention of the KIR3DL1-n alleles enables education but protects NK cells from inhibition by cognate HLA-Bw4 presented in trans.