Abstract
Author SummaryImmune cells survey their local environment and an immunological response can be activated when an appropriate target cell or antigen-presenting cell is recognised by key cell surface molecules. Just how the multitude of protein–protein interactions work to regulate this decision is an ongoing question. Imaging technology has provided key insights, demonstrating that immune cell activation is often accompanied by the segregation of proteins at immune synapses. Natural killer (NK) cells are lymphocytes that can recognise and kill virally infected or tumour-transformed cells via the formation of a synapse that facilitates secretion of cytotoxic granules directed at the target cells. Key to understanding target cell recognition by NK cells is to establish how the balance of activating and inhibitory signals at the synapse leads to an appropriate response, e.g., to kill or spare a target cell. We found that when activating ligands are dominant on a target cell, NK cells stop migrating and spread lamellipodia across the target cell to form a large symmetrical synapse. If inhibitory signals dominate, the symmetry of the NK cell spreading response is broken and the stop signal is reversed, which reduces the time spent in contact with the target cell. Thus, NK cell activating and inhibitory signals regulate NK cell synapse symmetry and migration to determine whether an NK cell will kill or move on.
Highlights
Natural killer (NK) cells are lymphocytes that play an important role in defence against infections and cancer [1]
To readily compare activating and inhibitory NK cell synapses, we initially used the well-established model cell system of the NK cell line YTS transfected to express an inhibitory receptor KIR2DL1 (YTS/KIR2DL1) mixed with either untransfected 721.221 (221), which does not express endogenous HLA-A, -B, or -C, or transfectants of 221 (221/Cw6) expressing an inhibitory MHC ligand for KIR2DL1, HLA-Cw6. This system is well-established as functionally leading to NK cell activation or inhibition [13]
We have demonstrated that the balance of activating and inhibitory ligands is continually locally assessed by NK cells following contact with a target cell
Summary
Natural killer (NK) cells are lymphocytes that play an important role in defence against infections and cancer [1] They directly kill tumor-transformed or virally infected cells via the formation of a cytolytic synapse that facilitates polarisation and subsequent secretion of cytotoxic granules directed towards the target cell [2,3,4] and contribute to immunity through, for example, cytokine release [5]. NK cell activation is regulated by a balance of activating and inhibitory signals through a multitude of germ-line encoded receptors that recognise ligands expressed on the surface of other cells [6,7]. One way that cells become susceptible to NK cell lysis is through an upregulation of activating ligands at their surface. Activating receptors trigger signalling cascades via phosphorylation of ITAM or ITAM-like motifs encoded within activating receptors or, more commonly, within associated adaptor proteins, whereas inhibitory receptors contain ITIM motifs that recruit SH2 domain protein tyrosine phosphatases upon receptor engagement (recently reviewed in [6])
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