Graphical Abstract Highlights d Atlas of 512,595 cis-regulatory elements active in 86 immunologic cell types d Two classes of loci, controlled by either promoter-or enhancer-driven logic d Inference of enhancer elements that activate each gene across differentiation d Context-specificity of enhancer activation by transcription factors Pile-up traces of ATAC-seq signals in Itgax locus. Blue bars in the first row indicate the positions of identified peaks (Pval % 0.05) and the graph in the 2 nd row conservation score among vertebrates. RNA expression for Itgax (Cd11c) gene are indicated by barplots with * where RNA-seq data was not acquired.

Summary Recent studies demonstrate that natural killer (NK) cells have adaptive immune features. Here, we investigated the role of the costimulatory molecule DNAM-1 in the differentiation of NK cells in a mouse model of cytomegalovirus (MCMV) infection. Antibody blockade of DNAM-1 suppressed the expansion of MCMV-specific Ly49H+ cells during viral infection and inhibited the generation of memory NK cells. Similarly, DNAM-1-deficient (Cd226−/−) Ly49H+ NK cells exhibited intrinsic defects in expansion and differentiation into memory cells. Src-family tyrosine kinase Fyn and serine -threonine protein kinase C isoform eta (PKCη) signaling through DNAM-1 played distinct roles in the generation of MCMV-specific effector and memory NK cells. Thus, cooperative signaling through DNAM-1 and Ly49H are required for NK cell-mediated host defense against MCMV infection.

Immunological memory has traditionally been regarded as a unique feature of the adaptive immune response, mediated in an antigen-specific manner by T and B lymphocytes. All other hematopoietic cells, including natural killer (NK) cells, are classified as innate immune cells, which have been considered short-lived but can respond rapidly against pathogens in a manner not thought to be driven by antigen. Interestingly, NK cells have recently been shown to survive long term after antigen exposure and subsequently mediate antigen-specific recall responses. In this review, we will address the similarities between, and the controversies surrounding, three major viewpoints of NK memory that have arisen from these recent studies: (i) MCMV (mouse cytomegalovirus)-induced memory; (ii) cytokine-induced memory; (iii) liver-restricted memory cells.

Natural killer (NK) cells provide important host defense against viruses and can differentiate into self-renewing memory NK cells after infection, alloantigen stimulation, and cytokine stimulation. Here, we investigated the role of the IL-33 receptor ST2 in the differentiation of NK cells during mouse cytomegalovirus (MCMV) infection. Although ST2-deficient (Il1rl1−/−) Ly49H+ NK cells develop normally and differentiate into memory cells after MCMV infection, naïve and memory Il1rl1−/− Ly49H+ NK cells exhibited profound defects in MCMV-specific expansion, resulting in impaired protection against MCMV challenge. Additionally, IL-33 enhanced m157 antigen-specific proliferation of Ly49H+ NK cells in vitro. Thus, an IL-33-ST2 signaling axis in NK cells contributes to host defense against MCMV.

Nabekura and Lanier demonstrate that two distinct long-lived NK cell subsets with different functional properties differentiate during mouse model of cytomegalovirus (MCMV) infection. NK cells expressing the MCMV-specific Ly49H receptor differentiated into memory NK cells and Ly49H− NK cells differentiated into cytokine-activated NK cells. Memory NK cells show enhanced effector function, whereas cytokine-activated NK cells persisted better in an MCMV-free environment.

Acute graft-versus-host disease (GVHD) is a life-threatening complication following bone marrow transplantation; however, no effective molecular-targeting therapy has been determined. Here, we show that mice that received allogeneic splenocytes deficient in DNAX accessory molecule-1 (DNAM-1) had significantly milder GVHD and lower mortality than those that received allogeneic WT splenocytes. Donor CD8 + T cells deficient in DNAM-1 showed significantly less proliferation and infiltration of the liver and intestines of recipient mice and produced less IFN-γ after coculture with allogeneic splenocytes than WT CD8 + T cells. Mice prophylactically treated with an anti-DNAM-1 antibody showed milder GVHD and lower mortality than those treated with a control antibody. Moreover, treatment with a single administration of the antibody after the overt onset of GVHD ameliorated GVHD and prolonged survival. Finally, we show that the anti-DNAM-1 antibody therapy also ameliorated the overt GVHD in lethally irradiated mice after MHC-matched, minor antigen-mismatched bone marrow transplantation. These results indicate that DNAM-1 plays an important role in the development of GVHD and is an ideal molecular target for therapeutic approaches to GVHD. costimulation | bone marrow transplant

Although type 1 innate lymphoid cells (ILC1s) have been originally found as liver-resident ILCs, their pathophysiological role in the liver remains poorly investigated. Here, we demonstrated that carbon tetrachloride (CCl 4 ) injection into mice activated ILC1s, but not natural killer (NK) cells, in the liver. Activated ILC1s produced interferon-g (IFN-g) and protected mice from CCl 4 -induced acute liver injury. IFN-g released from activated ILC1s promoted the survival of hepatocytes through upregulation of Bcl-xL. An activating NK receptor, DNAM-1, was required for the optimal activation and IFN-g production of liver ILC1s. Extracellular adenosine triphosphate accelerated interleukin-12-driven IFN-g production by liver ILC1s. These findings suggest that ILC1s are critical for tissue protection during acute liver injury.

Nabekura and Lanier provide evidence that alloantigen stimulation of mouse NK cells promotes the in vivo expansion and generation of memory-like NK cells. NK cells expressing the activating Ly49D receptor preferentially expand and differentiate when challenged with allogeneic cells in an inflammatory environment, but this can be suppressed if NK cells also express the inhibitory Ly49A receptor which recognizes the same ligand. Recall responses were driven by expression of activating Ly49 receptors and regulated by inhibitory MHC I receptors.