Nanoscale spatio-mechanical regulation of the immune signaling in cytotoxic lymphocytes.
2Ilse Katz Institute for Nanoscale Science & Technology, Ben-Gurion University of the Negev
3The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev
It has been long known that cytotoxic lymphocytes – the sentinels of our immune system – differentiate between pathogens and healthy cells by sensing environmental chemical cues, which are delivered by the ligands expressed on the surface target cells. Yet, it is becoming progressively clear that lymphocytes also sense physical environmental cues, such as ligand arrangement, mechanical stiffness, and topography. Recently, we explored the role of the ligand arrangement in the immune function of Natural Killer (NK) cells using nanoengineered stimulating platforms based on patterned arrays of ligands. The first generation of such platforms was based on arrays of nanoimprinted metallic nanodots functionalized with activating ligands, which allowed us to discover the minimal spatial requirement of ~ 1 ligand per sq. micron needed for the activation of NK cells[1]. The next, more advanced generation of arrays came to examine how the segregation between activating and inhibitory ligands affects the inhibition of activating signaling in NK cells. The platform was based on ordered arrays of nanodots of two metals selectively functionalized with activating and inhibitory ligands, whose segregation was systematically tuned between 0 nm to 40 nm[2]. Surprisingly, we found that inhibition efficiency increased with the spacing between the ligands within the probed range and rationalized this finding by physical modeling of the ligand-receptor binding kinetics.
We also studied the role of environmental elasticity and topography in the function of cytotoxic lymphocytes. Here, we engineered a stimulating platform based on ligand functionalized nanowires. The nanowires deliver chemical, nano-topographical, and mechanical cues, whose combination produced an enhanced immune response of NK cells [3]. While patterned in microdomains, these nanowires spatially guide the cytotoxic activity of NK cells [4]. To separately reveal the effect of each cue, we recently stimulated NK cells and CD8+ T cells on nanowires with varied length and bending moduli and found that these physical parameters of nanowires greatly affect the signaling and the immune function of the lymphocytes [5],[6]. Overall, our work provides an important insight into the way the physical cues regulate the function of NK cells and T cells.