BACKGROUND

ABSTRACT Immune synapses (IS) are supramolecu-lar clusters providing intercellular communication among cells of the immune system. While the physio-logical role and consequences of IS formation are beginning to be understood, these studies have given rise to a new research topic in the biology of lympho-cyte interactions: synaptic transfer of proteins between lymphocytes. During natural killer (NK) cell immuno-surveillance, clustering and transfer of receptor and ligand molecules have been observed at both the inhib-itory and cytotoxic NK cell immune synapse (NK-IS). The transfer of activating receptors seems to be asso-ciated with receptor distribution to thin membrane connective structures (MCS)/nanotubes that communi-cate effector and susceptible target cells. Strikingly, bidirectional transfer of the activating receptor NKG2D and its cellular ligand MICB correlates with a reduction in NK cell cytotoxic function. In this regard, synaptic uptake of MICB may represent a novel strategy of tumor immune evasion. Finally, synaptic acquisition of receptors by NK cells may also favor the spread of pathogens. In this review we discuss possible mecha-nisms of synaptic protein transfer and propose differ-ent testable hypotheses about the physiological and pathological significance of this process for NK cell function.—Roda-Navarro, P., Reyburn, H. T. Intercel-lular protein transfer at the NK cell immune synapse: mechanisms and physiological significance. FASEB J