The bone marrow is patrolled by NK cells that are primed and expand in response to systemic viral activation

• Published in: European journal of immunology 2018-07, Vol.48 (7), p.1137-1152
• Main Authors: Milo, Idan, Blecher‐Gonen, Ronnie, Barnett‐Itzhaki, Zohar, Bar‐Ziv, Raz, Tal, Orna, Gurevich, Irina, Feferman, Tali, Drexler, Ingo, Amit, Ido, Bousso, Philippe, Shakhar, Guy
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Ly - genetics; Bone marrow; Bone Marrow - immunology; Cell Differentiation; Cell migration; Cell Movement; Cell Proliferation; Cells, Cultured; Cellular proliferation; Cytotoxicity; Cytotoxicity, Immunologic; Dendritic cells; Dendritic Cells - immunology; Effector cells; Granzyme B; Granzymes - metabolism; Immune response; Immune system; Killer Cells, Natural - immunology; Lymphocyte Activation; Lymphocyte receptors; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy; Molecular chains; Natural Cytotoxicity Triggering Receptor 1 - genetics; NK cells; Poly I-C - immunology; Polyinosinic:polycytidylic acid; Post-transcription; Ribonucleic acid; RNA; Two‐photon imaging; Viremia; Viremia - immunology; Virus Activation
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201747378

The bone marrow hosts NK cells whose distribution, motility and response to systemic immune challenge are poorly understood. At steady state, two‐photon microscopy of the bone marrow in Ncr1gfp/+ mice captured motile NK cells interacting with dendritic cells. NK cells expressed markers and effector molecules of mature cells. Following poly (I:C) injection, RNA‐Seq of NK cells revealed three phases of transcription featuring immune response genes followed by posttranscriptional processes and proliferation. Functionally, poly (I:C) promoted upregulation of granzyme B, enhanced cytotoxicity in vitro and in vivo, and, in the same individual cells, triggered proliferation. Two‐photon imaging revealed that the proportion of sinusoidal NK cells decreased, while at the same time parenchymal NK cells accelerated, swelled and divided within the bone marrow. MVA viremia induced similar responses. Our findings demonstrate that the bone marrow is patrolled by mature NK cells that rapidly proliferate in response to systemic viral challenge while maintaining their effector functions. At steady NK cells in the BM contain mature effectors that patrol the sinusoids and parenchyma. Following systemic activation NK cells upregulate granzyme B, leave the sinusoids, swell and divide in the BM parenchyma.