Mechanosensation and Mechanotransduction in Natural Killer Cells

Abstract

Natural killer (NK) cells are a main subset of innate lymphocytes that contribute to host immune protection against viruses and tumors by mediating target cell killing and secreting a wide array of cytokines. Their functions are finely regulated by a balance between activating and inhibitory receptors and involve also adhesive interactions. Mechanotransduction is the process in which physical forces sensed by mechanosensors are translated into chemical signaling. Herein, we report findings on the involvement of this mechanism that is mainly mediated by actin cytoskeleton, in the regulation of NK cell adhesion, migration, tissue infiltration and functions. Actin represents the structural basis for NK cell immunological synapse (NKIS) and polarization of secretory apparatus. NK-target cell interaction involves the formation of both uropods and membrane nanotubes that allow target cell interaction over long distances. Actin retrograde flow (ARF) regulates NK cell signaling and controls the equilibrium between activation versus inhibition. Activating NKIS is associated with rapid lamellipodial ARF, whereas lower centripetal actin flow is present during inhibitory NKIS where β actin can associate with the tyrosine phosphatase SHP-1. Overall, a better knowledge of mechanotransduction might represent a future challenge: Realization of nanomaterials tailored for NK cells, would be important to translate in vitro studies in in vivo new immunotherapeutic approaches.

Lung Cancer Induces NK Cell Contractility and Cytotoxicity Through Transcription Factor Nuclear Localization

“…Here, we provide the first evidence that human circulating immune cells are mechanosensitive and harness contractility as a means to induce nuclear translocation of transcription factors to elicit cytotoxicity against NSCLCs. This may explain why previous studies showed a positive graded response of immune response genes (including IFNG ) when immune cells (e.g., T-cells) were cultured on substrates of increasing stiffness ( Saitakis et al, 2017 ; Santoni et al, 2021 ). Also, our findings help explain why an increase in osmolarity due to hemorrhages ( Pirkle and Gann, 1976 ) can result in the activation of infiltrating NK cells that exhibit increased cytotoxicity and chemokine production versus peripheral NK cells ( Li et al, 2020 ).…”

“…For example, both the activating receptors, NKG2D and DNAM-1, are known to induce actin polymerization through Vav1 ( Xiong et al, 2015 ), which will influence the dynamism of the NK cytoskeletal network. Likewise, the recognition of target cells through β1 and β2 integrins will most likely synergize mechano-responsively in NK cells ( Zhang et al, 2020 ; Santoni et al, 2021 ).…”

“…However, there is no evidence on whether the cytoplasmic/nuclear localization of transcription factors can be directly influenced by the perturbation of cellular force in non-adherent circulating immune cells like NK when undergoing anti-cancer activities. The activation of NK cells requires actin retrograde flow ( Matalon et al, 2018 ; Santoni et al, 2021 ) and the convergence and activation of various contractility-promoting proteins such as myosin IIA ( Krzewski et al, 2006 ). Moreover, degranulation of NK cells requires Arp2/3-mediated cytoskeleton rearrangement ( Carisey et al, 2018 ; Santoni et al, 2021 ).…”

“…The activation of NK cells requires actin retrograde flow ( Matalon et al, 2018 ; Santoni et al, 2021 ) and the convergence and activation of various contractility-promoting proteins such as myosin IIA ( Krzewski et al, 2006 ). Moreover, degranulation of NK cells requires Arp2/3-mediated cytoskeleton rearrangement ( Carisey et al, 2018 ; Santoni et al, 2021 ). These observations hint that cellular contractility, which awaits exploration, may play a role in regulating protein localization in the activation of NK cells, especially since NK cells harbour abundant cytoplasmic content ( Carpen et al, 1982 ).…”

Myosin 1g and 1f: A Prospective Analysis in NK Cell Functions

“…On the other hand, activation signals are given by activation receptors, for example, Ly49 (D, H, L) and KIR isoforms, NKG2D, and natural cytotoxic receptors such as NKp30 and NKp44 in humans and NKp46 in humans and mice ( 7 , 10 ). Additionally, LFA-1, β1, and β2 integrins can also regulate NK cell function ( 42 ), which we will address later. Signaling of activation and inhibition receptors regulate several NK cells functions, for example, degranulation, morphological modifications to increase NK-target cell contacts, cell migration, and cytokine release.…”