The NK Cell Secretome Under Activating and Inhibitory Conditions

Abstract

Natural killer cells are key effectors in the innate immune response, killing malignant and infected cells by forming immune synapses and releasing a lethal hit of lytic molecules and Extracellular Vesicles (EVs). Using a novel imaging approach termed shadow imaging, this study enabled the detailed spatial investigation of synaptic secretions and revealed stimulus-dependent modes of EV release. Stimulation by monoclonal antibodies increased EV secretion compared with native ligands both in intensity and in the area covered within the synapse relative to perforin. This investigation also unravelled differences in EV secretion timing. NKp30 stimulation led to quick EV secretion followed by slower perforin release, while the engagement of NKG2D provoked a sustained accumulation of perforin and EVs at the synapse over time. Remarkably, the study uncovered a potentially novel role for the inhibitory receptor NKG2A: it inhibited NK cell activation as expected but enhanced EV release in the presence of ICAM-1 or ICAM-1 and αNKp30. These EVs occasionally appeared in characteristic linear trails and their secretion depended on transport mediated by Rab27a and NKG2A ligation and downstream signalling. Altogether, these findings provide new insights into the temporal and receptor-specific aspects of NK cell secretions and further our understanding of NK cell biology.

Date of Award	3 Apr 2025
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Mark Travis (Main Supervisor)