Open AccessMolecular-scale spatio-chemical control of the activating-inhibitory signal integration in NK cells
Author(s) -
Esti Toledo,
Guillaume Le Saux,
Avishay Edri,
Long Li,
Maor Rosenberg,
Yossi Keidar,
Viraj Bhingardive,
Olga Radinsky,
Uzi Hadad,
Carmelo Di Primo,
Thierry Buffeteau,
AnaSunčana Smith,
Angel Porgador,
Mark Schvartzman
Publication year - 2021
Publication title -
science advances
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.928
H-Index - 146
ISSN - 2375-2548
DOI - 10.1126/sciadv.abc1640
Subject(s) - inhibitory postsynaptic potential , signal (programming language) , receptor , inhibitory control , scale (ratio) , signal pathway , control (management) , chemistry , computer science , microbiology and biotechnology , biology , neuroscience , signal transduction , physics , biochemistry , artificial intelligence , cognition , quantum mechanics , programming language
The role of juxtaposition of activating and inhibitory receptors in signal inhibition of cytotoxic lymphocytes remains strongly debated. The challenge lies in the lack of tools that allow simultaneous spatial manipulation of signaling molecules. To circumvent this, we produced a nanoengineered multifunctional platform with molecular-scale spatial control of ligands, which was applied to elucidate KIR2DL1-mediated inhibition of NKG2D signaling-receptors of natural killer cells. This platform was conceived by bimetallic nanodot patterning with molecular-scale registry, followed by a ternary functionalization with distinct moieties. We found that a 40-nm gap between activating and inhibitory ligands provided optimal inhibitory conditions. Supported by theoretical modeling, we interpret these findings as a consequence of the size mismatch and conformational flexibility of ligands in their spatial interaction. This highly versatile approach provides an important insight into the spatial mechanism of inhibitory immune checkpoints, which is essential for the rational design of future immunotherapies.