Format

Send to

Choose Destination
Nat Commun. 2019 Jan 31;10(1):514. doi: 10.1038/s41467-019-08384-x.

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

Author information

1
The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway.
2
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0310, Oslo, Norway.
3
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14186, Stockholm, Sweden.
4
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0310, Oslo, Norway.
5
Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, 0318, Oslo, Norway.
6
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Munich (LMU), Munich, 80336, Germany.
7
Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0310, Norway.
8
Genomics Core Facility, Department of Core Facilities, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, 0310, Norway.
9
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0424, Oslo, Norway.
10
Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177, Stockholm, Sweden.
11
Department of Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK.
12
The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway. k.j.malmberg@medisin.uio.no.
13
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0310, Oslo, Norway. k.j.malmberg@medisin.uio.no.
14
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, 14186, Stockholm, Sweden. k.j.malmberg@medisin.uio.no.

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central Icon for Norwegian BIBSYS system
Loading ...
Support Center