Cardiac macrophages are crucial for tissue repair after cardiac injury but are not well characterized. Here we identify four populations of cardiac macrophages. At steady state, resident macrophages ...were primarily maintained through local proliferation. However, after macrophage depletion or during cardiac inflammation, Ly6chi monocytes contributed to all four macrophage populations, whereas resident macrophages also expanded numerically through proliferation. Genetic fate mapping revealed that yolk-sac and fetal monocyte progenitors gave rise to the majority of cardiac macrophages, and the heart was among a minority of organs in which substantial numbers of yolk-sac macrophages persisted in adulthood. CCR2 expression and dependence distinguished cardiac macrophages of adult monocyte versus embryonic origin. Transcriptional and functional data revealed that monocyte-derived macrophages coordinate cardiac inflammation, while playing redundant but lesser roles in antigen sampling and efferocytosis. These data highlight the presence of multiple cardiac macrophage subsets, with different functions, origins, and strategies to regulate compartment size.
•Yolk-sac and fetal monocyte progenitors give rise to adult cardiac macrophages•Yolk-sac macrophages persisted into adulthood only in the heart, liver, and brain•Embryonically established resident macrophages can be replaced by blood monocytes•Cardiac macrophages differentially activate T cells and take up dying cardiomyocytes
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
It is thought that monocytes rapidly differentiate to macrophages or dendritic cells (DCs) upon leaving blood. Here we have shown that Ly-6C+ monocytes constitutively trafficked into skin, lung, and ...lymph nodes (LNs). Entry was unaffected in gnotobiotic mice. Monocytes in resting lung and LN had similar gene expression profiles to blood monocytes but elevated transcripts of a limited number of genes including cyclo-oxygenase-2 (COX-2) and major histocompatibility complex class II (MHCII), induced by monocyte interaction with endothelium. Parabiosis, bromodoxyuridine (BrdU) pulse-chase analysis, and intranasal instillation of tracers indicated that instead of contributing to resident macrophages in the lung, recruited endogenous monocytes acquired antigen for carriage to draining LNs, a function redundant with DCs though differentiation to DCs did not occur. Thus, monocytes can enter steady-state nonlymphoid organs and recirculate to LNs without differentiation to macrophages or DCs, revising a long-held view that monocytes become tissue-resident macrophages by default.
•Ly-6C+ not Ly-6C− monocytes enter tissues in the steady state•Tissue monocytes can retain monocyte profile without becoming macrophages or DCs•Tissue monocytes may mediate antigen surveillance: they are MHCII+ and migrate to LNs•MHCII induction on tissue monocytes can be driven by interactions with endothelium
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Natural killer (NK) cells, like B and T lymphocytes, are potent effector cells that are crucial for immunity to tumors and infections. These effector responses must be controlled to avoid inadvertent ...attack against normal self. Yet, the mechanisms that guide NK cell tolerance differ from those guiding T and B cell tolerance. Here, we discuss how NK cells are licensed by self-MHC class I molecules through their inhibitory receptors which results in NK cell functional competence to be triggered through their activation receptors. We discuss recent data with respect to issues related to licensing, thereby providing a framework for unifying concepts on NK cell education.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Uterine Natural Killer Cells Sojka, Dorothy K; Yang, Liping; Yokoyama, Wayne M
Frontiers in immunology,
05/2019, Volume:
10
Journal Article
Peer reviewed
Open access
Natural killer (NK) cells are members of a rapidly expanding family of innate lymphoid cells (ILCs). While most previously studied NK cells were derived from the mouse spleen and circulate in the ...blood, recently others and we found tissue-resident NK (trNK) cells in many tissues that resemble group 1 ILCs (ILC1s). During pregnancy, NK cells are the most abundant lymphocytes in the uterus at the maternal-fetal interface and are involved in placental vascular remodeling. Prior studies suggested that these uterine NK (uNK) cells are mostly derived from circulating NK cells. However, the murine virgin uterus contains mostly trNK cells and it has been challenging to determine their contribution to uNK cells in pregnancy as well as other potential function(s) of uNK cells due to the dynamic microenvironment in the pregnant uterus. This review focuses on the origins and functions of the heterogeneous populations of uNK cells during the course of murine pregnancy.
Natural killer (NK) cells were originally defined as effector lymphocytes of innate immunity endowed with constitutive cytolytic functions. More recently, a more nuanced view of NK cells has emerged. ...NK cells are now recognized to express a repertoire of activating and inhibitory receptors that is calibrated to ensure self-tolerance while allowing efficacy against assaults such as viral infection and tumor development. Moreover, NK cells do not react in an invariant manner but rather adapt to their environment. Finally, recent studies have unveiled that NK cells can also mount a form of antigen-specific immunologie memory. NK cells thus exert sophisticated biological functions that are attributes of both innate and adaptive immunity, blurring the functional borders between these two arms of the immune response.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The type I interferon (IFN) response protects cells from viral infection by inducing hundreds of interferon-stimulated genes (ISGs), some of which encode direct antiviral effectors. Recent screening ...studies have begun to catalogue ISGs with antiviral activity against several RNA and DNA viruses. However, antiviral ISG specificity across multiple distinct classes of viruses remains largely unexplored. Here we used an ectopic expression assay to screen a library of more than 350 human ISGs for effects on 14 viruses representing 7 families and 11 genera. We show that 47 genes inhibit one or more viruses, and 25 genes enhance virus infectivity. Comparative analysis reveals that the screened ISGs target positive-sense single-stranded RNA viruses more effectively than negative-sense single-stranded RNA viruses. Gene clustering highlights the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS, also known as MB21D1) as a gene whose expression also broadly inhibits several RNA viruses. In vitro, lentiviral delivery of enzymatically active cGAS triggers a STING-dependent, IRF3-mediated antiviral program that functions independently of canonical IFN/STAT1 signalling. In vivo, genetic ablation of murine cGAS reveals its requirement in the antiviral response to two DNA viruses, and an unappreciated contribution to the innate control of an RNA virus. These studies uncover new paradigms for the preferential specificity of IFN-mediated antiviral pathways spanning several virus families.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We examine the features, origin, turnover, and gene expression of pancreatic macrophages under steady state. The data distinguish macrophages within distinct intrapancreatic microenvironments and ...suggest how macrophage phenotype is imprinted by the local milieu. Macrophages in islets of Langerhans and in the interacinar stroma are distinct in origin and phenotypic properties. In islets, macrophages are the only myeloid cells: they derive from definitive hematopoiesis, exchange to a minimum with blood cells, have a low level of self-replication, and depend on CSF-1. They express Il1b and Tnfa transcripts, indicating classical activation, M1, under steady state. The interacinar stroma contains two macrophage subsets. One is derived from primitive hematopoiesis, with no interchange by blood cells and alternative, M2, activation profile, whereas the second is derived from definitive hematopoiesis and exchanges with circulating myeloid cells but also shows an alternative activation profile. Complete replacement of islet and stromal macrophages by donor stem cells occurred after lethal irradiation with identical profiles as observed under steady state. The extraordinary plasticity of macrophages within the pancreatic organ and the distinct features imprinted by their anatomical localization sets the base for examining these cells in pathological conditions.
Identification of type 1 innate lymphoid cells (ILC1s) has been problematic. The transcription factor Hobit encoded by
has been proposed as a major driver of ILC1 programs. Using
reporter mice, we ...showed that correlation of Hobit expression with ILC1s is tissue- and context-dependent. In liver and intestinal mucosa,
expression correlated well with ILC1s; in salivary glands,
was coexpressed with the natural killer (NK) master transcription factors Eomes and TCF1 in a unique cell population, which we call ILC1-like NK cells; during viral infection,
was induced in conventional NK cells of spleen and liver. The impact of
deletion on ILC1s and NK cells was also multifaceted, including a marked decrease in granzyme- and interferon-gamma (IFNγ)-producing ILC1s in the liver, slightly fewer ILC1s and more Eomes
TCF1
ILC1-like NK cells in salivary glands, and only reduced production of granzyme B by ILC1 in the intestinal mucosa. NK cell-mediated control of viral infection was unaffected. We conclude that Hobit has two major impacts on ILC1s: It sustains liver ILC1 numbers, while promoting ILC1 functional maturation in other tissues by controlling TCF1, Eomes, and granzyme expression.
Cytokine-induced memory-like natural killer cells Cooper, Megan A; Elliott, Julie M; Keyel, Peter A ...
Proceedings of the National Academy of Sciences - PNAS,
02/2009, Volume:
106, Issue:
6
Journal Article
Peer reviewed
Open access
The mammalian immune response to infection is mediated by 2 broad arms, the innate and adaptive immune systems. Innate immune cells are a first-line defense against pathogens and are thought to ...respond consistently to infection, regardless of previous exposure, i.e., they do not exhibit memory of prior activation. By contrast, adaptive immune cells display immunologic memory that has 2 basic characteristics, antigen specificity and an amplified response upon subsequent exposure. Whereas adaptive immune cells have rearranged receptor genes to recognize the universe of antigens, natural killer (NK) cells are innate immune lymphocytes with a limited repertoire of germ-line encoded receptors for target recognition. NK cells also produce cytokines such as IFN-gamma (IFN-γ) to protect the host during the innate response to infection. Herein, we show that cytokine-activated NK cells transferred into naïve hosts can be specifically detected 7-22 days later when they are phenotypically similar to naïve cells and are not constitutively producing IFN-γ. However, they produce significantly more IFN-γ when restimulated. This memory-like property is intrinsic to the NK cell. By contrast, memory-like NK cells do not express granzyme B protein and kill targets similarly to naïve NK cells. Thus, these experiments identify an ability of innate immune cells to retain an intrinsic memory of prior activation, a function until now attributed only to antigen-specific adaptive immune cells.
Natural killer (NK) cells have potent capacities to immediately kill cellular targets and produce cytokines that may potentially damage normal self‐tissues unless they are kept in check. Such ...tolerance mechanisms are incompletely understood. Here we discuss recent studies suggesting that NK cells undergo a host major histocompatibility complex (MHC) class I‐dependent functional maturation process, termed ‘licensing’. Ironically, licensing directly involves inhibitory receptors that recognize target cell MHC class I molecules and block activation of NK cells in effector responses. This process results in two types of tolerant NK cells: functionally competent (licensed) NK cells, whose effector responses are inhibited by self‐MHC class I molecules through the same receptors that conferred licensing, and functionally incompetent (unlicensed) NK cells.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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