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Modulation of Secretory Lysosomes During NK Cell Education Leads to Accumulation of Granzyme B and Enhanced Functional Potential

By Jodie P Goodridge, Benedikt Jacobs, Michelle L Saetersmoen, Dennis Clement, Trevor Clancy, Ellen Skarpen, Andreas Brech, Johannes Landskron, Christian Grimm, Aline Pfefferle, Leonardo Meza-Zepeda, Susanne Lorenz, Merete Thune Wiiger, William E Louch, Eivind Heggernes Ask, Lisa L Liu, Vincent Yi Sheng Oei, Una Kjällquist, Sten Linnarsson, Sandip Patel, Kjetil Taskén, Harald Stenmark, Karl-Johan Malmberg

Posted 24 Apr 2018
bioRxiv DOI: 10.1101/305862 (published DOI: https://www.nature.com/articles/s41467-019-08384-x)

Inhibitory signaling during natural killer (NK) cell education translates into increased responsiveness to activation; however the intracellular mechanism for functional tuning by inhibitory receptors remains unclear. We found that educated NK cells expressing self-MHC specific inhibitory killer cell immunoglobulin-like receptors (KIR) show accumulation of granzyme B, localized in dense-core secretory lysosomes, converged close to the centrosome. This discrete morphological phenotype persists in self-KIR+ NK cells independently of transcriptional programs that regulate effector function, metabolism and lysosomal biogenesis. The granzyme-B dense, large secretory lysosomes in self-KIR+ NK cells were efficiently released upon target cell recognition, contributing to their enhanced cytotoxic capacity. Secretory lysosomes are part of the acidic lysosomal compartment, which has been shown to channel calcium and mediate intracellular signalling in several cell types. Interference of signaling from acidic Ca2+ stores in primary NK cells reduced both target-specific Ca2+-flux, degranulation and cytokine production. Furthermore, inhibition of PI(3,5)P2 synthesis or genetic silencing of the PI(3,5)P2-regulated lysosomal Ca2+-channel TRPML1 led to increased levels of granzyme B and enhanced functional potential. These results indicate an intrinsic role for lysosomal homeostasis in NK cell education.

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