Natural Killer (NK) cells play an important role in the early immune response to cancer. The NKp44 activating receptor is the only Natural Cytotoxicity Receptor that is expressed exclusively by primate NK cells; yet, its cellular ligands remain largely unknown. Proliferating Cell Nuclear Antigen (PCNA) is overexpressed in cancer cells. We show that the NKp44 receptor recognizes PCNA. Their interaction inhibits NK cell function through the NKp44-Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM). The physical interaction of NKp44 and PCNA is enabled by recruitment of target cell PCNA to the NK immunological synapse. We demonstrate that PCNA promotes cancer survival by immune evasion through inhibition of NKp44-mediated NK cell attack.

function of cells. [8] These forces have different origins, such as actin dynamics, [9] and play important roles at different stages of the lymphocyte immune activity. Initial sampling of antigens on the surface of antigen presenting cells (APCs), as well as activation of immunoreceptors, strongly depends on actin polymerization and dynamics. [10] Moreover, immunoreceptors recognize antigens under mechanical load to discriminate between high-affinity and low-affinity antigens. [11] Once activated, the receptor-antigen complexes on the lymphocyte-APC interface are driven by retrograde actin flow and myosin contraction into highly regulated structures termed immune synapse, whose forces affect the inside-out signaling of lymphocytes. Today, mechanical forces in immune system are a subject of emerging research, which has so far mostly focused on T cells and B cells. [12,13] Studying mechanical forces in cells is challenging, because these forces have relatively low magnitude -mostly at the nanoNewton scale, and often span over miniature regions sized down to the molecular scale. Existing tools include optical traps, [14,15] micropipettes, [16] and atomic force microscopy (AFM), [17,18] which, however, apply and detect forces only at single point on the cell membrane, and do not overview the mechanical behavior of the entire cell. Alternatively, traction force microscopy, which determines the displacement of microbeads embedded in hydrogel surface for cell spreading, maps forces of entire cells, [19][20][21] however, it can hardly detect the exact bead movement since the beads are distributed randomly, and their resting position is unknown. Furthermore, analysis of bead movement requires complex force calculations based on elasticity theory. [22] These constrains can be overcome by elastomeric micropillars for cell spreading, which allow facile mapping of force distribution within cells. [23] Furthermore, micropillars can be functionalized with biomolecules that yield chemical stimuli for various cell functions, such as adhesion [24,25] or immune response, [26] and thereby allow integration of mechanical and biochemical cues. However, the advantages of elastic micropillars come at the expense of their spatial and mechanical resolution. Indeed, poly(dimethyl siloxane) (PDMS) -material of choice for micropillar fabrication -is limited for the fabrication of pillars with micrometerscale size and aspect ratio of 3:1, for which sensing forces below Cells sense their environment by transducing mechanical stimuli into biochemical signals. Commonly used tools to study cell mechanosensing provide limited spatial and force resolution. Here, a novel nanowire-based platform for monitoring cell forces is reported. Nanowires are functionalized with ligands for cell immunoreceptors, and they are used to explore the mechanosensitivity of natural killer (NK) cells. In particular, it is found that NK cells apply centripetal forces to nanowires, and that the nanowires stimulate cell contraction. Based on the nanowire deformation, it is...

A transepithelial pathway delivers succinate to macrophages, thus perpetuating their proinflammatory metabolic state Graphical abstract Highlights d Succinate uptake is elevated in macrophages to perpetuate their pro-inflammatory state d Na + -dependent transporters mediate transepithelial succinate delivery into macrophages d Succinate concentrations are elevated in the serum and feces of IBD patients d Succinate-metabolizing bacteria are altered in IBD patients

Natural killer (NK) cells play an important role in first-line defense against tumor and virus-infected cells. The activity of NK cells is tightly regulated by a repertoire of cell surface expressed inhibitory and activating receptors. NKp46 is a major NK cell-activating receptor that is involved in the elimination of target cells. NK cells form different types of synapses that result in distinct functional outcomes: cytotoxic, inhibitory, and regulatory. Recent studies revealed that complex integration of NK receptor signaling controls cytoskeletal rearrangement and other immune synapse-related events. However, the distinct nature by which NKp46 participates in NK immunological synapse formation and function remains unknown. In this study, we determined that NKp46 forms microclusters structures at the immune synapse between NK cells and target cells. Over-expression of human NKp46 is correlated with increased accumulation of F-actin mesh at the immune synapse. Concordantly, knock-down of NKp46 in primary human NK cells decreased recruitment of F-actin to the synapse. Live cell imaging experiments showed a linear correlation between NKp46 expression and lytic granules polarization to the immune synapse. Taken together, our data suggest that NKp46 signaling directly regulates the NK lytic immune synapse from early formation to late function.