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 LinnarssonSandip Patel, Kjetil Taskén, Harald Stenmark, Karl Johan Malmberg

Research output: Contribution to journalArticleResearchpeer-review

31 Citations (Scopus)

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 Ca 2+ stores in primary NK cells reduces target-specific Ca 2+ -flux, degranulation and cytokine production. Furthermore, inhibition of PI(3,5)P 2 synthesis, or genetic silencing of the PI(3,5)P 2 -regulated lysosomal Ca 2+ -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.

Original languageEnglish
Article number514
Number of pages15
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 31 Jan 2019
Externally publishedYes

Keywords

  • autoimmunity
  • innate immunity
  • ion channel signalling
  • NK cells

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