Know Thyself: NK-Cell Inhibitory Receptors Prompt Self-Tolerance, Education, and Viral Control

Abstract

Natural killer (NK) cells provide essential protection against viral infections. One of the defining features of this lymphocyte population is the expression of a wide array of variable cell surface stimulatory and inhibitory NK receptors (sNKR and iNKR, respectively). The iNKR are particularly important in terms of NK-cell education. As receptors specific for MHC class I (MHC I) molecules, they are responsible for self-tolerance and adjusting NK-cell reactivity based on the expression level of self-MHC I. The end result of this education is twofold: (1) inhibitory signaling tunes the functional capacity of the NK cell, endowing greater potency with greater education, and (2) education on self allows the NK cell to detect aberrations in MHC I expression, a common occurrence during many viral infections. Many studies have indicated an important role for iNKR and MHC I in disease, making these receptors attractive targets for manipulating NK-cell reactivity in the clinic. A greater understanding of iNKR and their ability to regulate NK cells will provide a basis for future attempts at translating their potential utility into benefits for human health.

Keywords: NK cells; education; immunity; inhibitory receptors; licensing; virus control.

Figure 1

Natural killer education primes NK cells for heightened effector function. (A) Inhibitory signaling serves a twofold purpose. On one hand, it can disrupt activation signals from sNKR at several intersections (e.g., SHP dephosphorylation of Vav, SHIP dephosphorylation of PIP₃, and c-Abl sequestration of Crk from activation complexes). On the other hand, it also serves to tune the reactivity of the NK cell to activating stimuli, either through unknown positive signals transmitted downstream of iNKR ligation (licensing model) or prevention of anergy (disarming model). One distinct benefit of self-specific iNKR that has been recently established is the ability to enhance sNKR inside-out signaling to LFA-1 to promote adhesion and target recognition. (B) The balance of signals in NK cells determines their reactivity. NK that do not receive inhibitory signals can be activated in response to inflammatory stimuli and conditions, but are generally less responsive to sNKR stimulation (in terms of cytokine production and cytotoxicity) than NK that receive iNKR input. Whether this occurs via a licensing mechanism, disarming mechanism, or both is still not fully worked out.

Figure 2

Viral manipulation of the MHC class I antigen processing and presentation. The presentation of self- and foreign-peptides on MHC class I molecules is integral to the regulation of both NK and CD8+ T cell immunity. Viruses have developed multiple strategies to interfere with class I antigen presentation, with the ultimate goal of evading both innate and adaptive immune recognition. Manipulation of class I molecules can occur at various stages of the class I expression pathway: (1) peptide antagonists produced during proteasomal degradation of cytoplasmic proteins dictate the affinity of class I interactions with iNKR and CD8+ TCR; (2) immunoevasins interfere with the proper loading and folding of the class I molecules, and even retain properly folded molecules in the ER; (3) viral proteins promote the export of class I molecules into the cytosol for proteasomal degradation or re-direct class I trafficking from the ER to endo-lysosomal compartments; (4) viral proteins promote the expression of classical and non-classical MHC molecules, as well as class I mimics, to specifically inhibit NK-cell activation.

Figure 3

Summary of proposed beneficial effects of licensed-NK cells. NK Licensing potentially impacts the immune response in a variety of ways. Benefits may manifest directly as NK specific recognition or indirectly via effects on their environment and other cells.