Cell biological steps and checkpoints in accessing NK cell cytotoxicity

Abstract

Natural killer (NK) cell-mediated cytotoxicity is governed by the formation of a lytic immune synapse in discrete regulated steps, which give rise to an extensive array of cellular checkpoints in accessing NK cell-mediated cytolytic defense. Appropriate progression through these cell biological steps is critical for the directed secretion of specialized secretory lysosomes and subsequent target cell death. Here we highlight recent discoveries in the formation of the NK cell cytolytic synapse as well as the molecular steps and cell biological checkpoints required for this essential host defense process.

Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control

“…Next, we investigated the dynamics of NK cell recognition and killing of target cells. Target cell killing is a tightly orchestrated event composed of multiple steps including recognition of the target cell, adhesion, and formation of an immunological synapse (IS), anchoring to the target with filamentous F-actin, convergence of granules to the microtubule organizing center (MTOC), polarization and trafficking of the MTOC toward the IS, degranulation, and finally detachment (40). By flow cytometry, 2DG did not significantly decrease NK cell recognition of potential targets, as demonstrated by normal conjugate formation between 2DG-treated NK cells and Ba/F3-m157 targets ( Figure 2B).…”

Microchip-Based Single-Cell Imaging Reveals That CD56dimCD57−KIR−NKG2A+ NK Cells Have More Dynamic Migration Associated with Increased Target Cell Conjugation and Probability of Killing Compared to CD56dimCD57−KIR−NKG2A− NK Cells

“…Thus, these observations propose that the high killing capacity of NKG2A + NK cells is linked to processes regulating events in the recognition phase of NK-target cell contact (26) where the threshold for lytic response is set, rather than events after cytotoxicity has been triggered.…”

CD56bright NK cells exhibit potent antitumor responses following IL-15 priming

“…Signaling through LFA-1 has been shown to activate ERK1/2 (43) (outside-in signaling), and enhanced ERK1/2 phosphorylation was observed in IL-15-primed CD56 bright NK cells trigged with K562 targets compared with control cells ( Figure 5C). Thus, IL-15 priming promotes integrin activation on CD56 bright NK cells, potentially allowing adhesion to target cells in the absence of signals from other activating receptors (39), and also enhances subsequent target-induced inside-out and outside-in signaling.…”

“…*P < 0.05, **P < 0.01. (33,39,40). Integrins typically exist in a bent conformation with low ligand-binding affinity.…”