We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Remodeling of secretory lysosomes during education tunes functional potential in NK cells.
- Authors
Goodridge, Jodie P.; Jacobs, Benedikt; Saetersmoen, Michelle L.; Clement, Dennis; Hammer, Quirin; Clancy, Trevor; Skarpen, Ellen; Brech, Andreas; Landskron, Johannes; Grimm, Christian; Pfefferle, Aline; Meza-Zepeda, Leonardo; Lorenz, Susanne; Wiiger, Merete Thune; Louch, William E.; Ask, Eivind Heggernes; Liu, Lisa L.; Oei, Vincent Yi Sheng; Kjällquist, Una; Linnarsson, Sten
- 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. Natural killer (NK) cells are functionally calibrated against self MHC during a process termed education. Here the authors show that NK cell education is associated with the accumulation of dense-core secretory lysosomes for expedited release of granzyme B and Ca2+ flux upon target recognition and NK cell activation.
- Publication
Nature Communications, 2019, Vol 10, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-08384-x