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Molecular-scale spatio-chemical control of the activating-inhibitory signal integration in NK cells

Toledo, Esti; Le Saux, Guillaume; Edri, Avishay; Li, Long; Rosenberg, Maor; Keidar, Yossi; Bhingardive, Viraj; Radinsky, Olga; Hadad, Uzi; Di Primo, Carmelo; Buffeteau, Thierry; Smith, Ana-Sunčana; Porgador, Angel; Schvartzman, Mark (2021) Molecular-scale spatio-chemical control of the activating-inhibitory signal integration in NK cells. Science advances, 7 (24). ISSN 2375-2548

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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 acti-vating and inhibitory ligands provided optimal inhibitory conditions. Supported by theoretical modeling, we in- terpret 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.

Item Type: Article
Uncontrolled Keywords: Cell Signaling
Subjects: NATURAL SCIENCES > Chemistry
Divisions: Division of Physical Chemistry
Depositing User: Ana Sunčana Smith
Date Deposited: 31 Dec 2021 10:09
DOI: 10.1126/sciadv.abc1640

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