Fig. 8

Model describing the distinct fates of NK cells during NK cell education. NK cells lacking self-specific receptors receive tonic stimulatory input through activating receptors and show poor functional responses, a process referred to as disarming⁵¹. We found that such cells exhibit lower levels of the granule matrix protein serglycin and effector molecules granzyme B and perforin and lack dense-core secretory lysosomes. One putative pathway downstream of activation receptor signaling is PI3K/AKT that stimulate the enzyme PIKfyve, which converts PI3P to PI(3,5)P₂ and thereby positively regulate the lysosome-specific Ca²⁺ channel TRPML1⁴¹. PIKfyve and TRPML1 are critically involved in lysosomal modulation in several cell types^{40, 41}. Inhibitory KIRs interfere with activation signals at a proximal level and thereby shut down any signals that could drive such lysosomal modulation. In support of this notion, we found that pharmacological interference with PIKfyve or silencing of TRPML1 replicated the educated state with enlarged lysosomes, increased granzyme B loads and more potent effector function. The secretory lysosome is part of the acidic Ca²⁺ stores and may thus potentiate receptor-mediated Ca²⁺ release from the ER^31,32,33,34. Interference with signaling from the acidic Ca²⁺ stores resulted in the loss of NK cell function. Thus, the accumulation of dense-core secretory lysosomes during NK cell education may contribute to the increased function, not only through the increased cytotoxic payload, but also through enhanced signaling from acidic Ca²⁺ stores