engleski

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

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.

Cell Signaling

This work was funded by the Multidisciplinary Research Grant—The Faculty of Health Science in Ben-Gurion University of the Negev, Israel Science Foundation, Individual Grant No. 1401/15, and Israel Science Foundations: F.I.R.S.T. Individual Grant No. 2058/18. SPR and PM-IRRAS analyses were performed with the financial help of COST Action CA15126. This work has benefited from the facilities and expertise of the Biophysical and Structural Chemistry platform at IECB, CNRS UMS3033, Inserm US001, Bordeaux University.