Remodeling of secretory lysosomes during education tunes functional potential in NK cells

Jodie P. Goodridge, Benedikt Jacobs, Michelle L. Saetersmoen, Dennis Clement, Quirin Hammer, 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 and Karl-Johan Malmberg ()
Additional contact information
Jodie P. Goodridge: University of Oslo
Benedikt Jacobs: University of Oslo
Michelle L. Saetersmoen: University of Oslo
Dennis Clement: University of Oslo
Quirin Hammer: Karolinska Institutet
Trevor Clancy: University of Oslo
Ellen Skarpen: Oslo University Hospital
Andreas Brech: Oslo University Hospital
Johannes Landskron: University of Oslo
Christian Grimm: University of Munich (LMU)
Aline Pfefferle: Karolinska Institutet
Leonardo Meza-Zepeda: Oslo University Hospital
Susanne Lorenz: Oslo University Hospital
Merete Thune Wiiger: University of Oslo
William E. Louch: Oslo University Hospital and University of Oslo
Eivind Heggernes Ask: University of Oslo
Lisa L. Liu: Karolinska Institutet
Vincent Yi Sheng Oei: University of Oslo
Una Kjällquist: Karolinska Institutet
Sten Linnarsson: Karolinska Institutet
Sandip Patel: University College London
Kjetil Taskén: University of Oslo
Harald Stenmark: Oslo University Hospital
Karl-Johan Malmberg: University of Oslo

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract 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. Secretory lysosomes are part of the acidic lysosomal compartment that mediates intracellular signalling in several cell types. Here we show that educated NK cells expressing self-MHC specific inhibitory killer cell immunoglobulin-like receptors (KIR) accumulate granzyme B in dense-core secretory lysosomes that converge close to the centrosome. This discrete morphological phenotype is independent of transcriptional programs that regulate effector function, metabolism and lysosomal biogenesis. Meanwhile, interference of signaling from acidic Ca2+ stores in primary NK cells reduces 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, leads to increased granzyme B and enhanced functional potential, thereby mimicking the educated state. These results indicate an intrinsic role for lysosomal remodeling in NK cell education.

Date: 2019
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DOI: 10.1038/s41467-019-08384-x

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