biostudies-literatureGoodridge JPBiotechnology and Biological Sciences Research Council514https://www.ebi.ac.uk/biostudies/studies/S-EPMC6355880biostudies-literatureUnknown10(1)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 NNature communicationsRemodeling of secretory lysosomes during education tunes functional potential in NK cells.PMC6355880BB/K000942/1BB/N01524X/1Louch WEMeza-Zepeda LLiu LLKjallquist ULandskron JGoodridge JPLorenz SClancy TPfefferle ATasken KHammer QPatel SWiiger MTSaetersmoen MLSkarpen EBrech AAsk EHJacobs BGrimm CMalmberg KJStenmark HClement DOei VYSLinnarsson SfalseRemodeling of secretory lysosomes during education tunes functional potential in NK cells.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 N2019-01-01T00:00:00Z2019 Jan2026-05-06T21:50:49.401Z2019-03-26T22:47:53ZS-EPMC63558803070527910.1038/s41467-019-08384-x