scholarly journals Modulation of the Effects of Lung Immune Response on Bone Marrow by Oral Antigen Exposure

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
P. Xavier-Elsas ◽  
C. L. C. A. Silva ◽  
L. Pinto ◽  
T. Queto ◽  
B. M. Vieira ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Lymphocytes ◽  
Ex Vivo ◽  
Allergen Challenge ◽  
Allergic Airway Inflammation ◽  
Oral Exposure ◽  
Wild Type ◽  
Homologous Antigen ◽  
Mutant Strains

Allergic airway inflammation is attenuated by oral tolerization (oral exposure to allergen, followed by conventional sensitization and challenge with homologous antigen), which decreases airway allergen challenge-induced eosinophilic infiltration of the lungs and bone marrow eosinophilia. We examined its effects on bone marrow eosinophil and neutrophil production. Mice of wild type (BP-2, BALB/c, and C57BL/6) and mutant strains (lacking iNOS or CD95L) were given ovalbumin (OVA) or water (vehicle) orally and subsequently sensitized and challenged with OVA (OVA/OVA/OVA and H2O/OVA/OVA groups, resp.). Anti-OVA IgG and IgE, bone marrow eosinophil and neutrophil numbers, and eosinophil and neutrophil production ex vivo were evaluated. T lymphocytes from OVA/OVA/OVA or control H2O/OVA/OVA donors were transferred into naïve syngeneic recipients, which were subsequently sensitized/challenged with OVA. Alternatively, T lymphocytes were cocultured with bone marrow eosinophil precursors from histocompatible sensitized/challenged mice. OVA/OVA/OVA mice of the BP-2 and BALB/c strains showed, relative to H2O/OVA/OVA controls, significantly decreased bone marrow eosinophil counts and ex vivo eosinopoiesis/neutropoiesis. Full effectiveness in vivo required sequential oral/subcutaneous/intranasal exposures to the same allergen. Transfer of splenic T lymphocytes from OVA/OVA/OVA donors to naive recipients prevented bone marrow eosinophilia and eosinopoiesis in response to recipient sensitization/challenge and supressed eosinopoiesis upon coculture with syngeneic bone marrow precursors from sensitized/challenged donors.

scholarly journals N-3-Hydroxy Dodecanoyl-DL-homoserine Lactone (OH-dDHL) Triggers Apoptosis of Bone Marrow-Derived Macrophages through the ER- and Mitochondria-Mediated Pathways

2021 ◽  
Vol 22 (14) ◽  
pp. 7565
Author(s):  
Kyungho Woo ◽  
Dong Ho Kim ◽  
Man Hwan Oh ◽  
Ho Sung Park ◽  
Chul Hee Choi
Keyword(s):  
Bone Marrow ◽  
Quorum Sensing ◽  
Deletion Mutant ◽  
Transmembrane Protein ◽  
Cell Communication ◽  
Homoserine Lactone ◽  
Host Responses ◽  
Wild Type ◽  
Mutant Strains

Quorum sensing of Acinetobacter nosocomialis for cell-to-cell communication produces N-3-hydroxy dodecanoyl-DL-homoserine lactone (OH-dDHL) by an AnoR/I two-component system. However, OH-dDHL-driven apoptotic mechanisms in hosts have not been clearly defined. Here, we investigated the induction of apoptosis signaling pathways in bone marrow-derived macrophages treated with synthetic OH-dDHL. Moreover, the quorum-sensing system for virulence regulation was evaluated in vivo using wild-type and anoI-deletion mutant strains. OH-dDHL decreased the viability of macrophage and epithelial cells in dose- and time-dependent manners. OH-dDHL induced Ca2+ efflux and caspase-12 activation by ER stress transmembrane protein (IRE1 and ATF6a p50) aggregation and induced mitochondrial dysfunction through reactive oxygen species (ROS) production, which caused cytochrome c to leak. Pretreatment with a pan-caspase inhibitor reduced caspase-3, -8, and -9, which were activated by OH-dDHL. Pro-inflammatory cytokine and paraoxonase-2 (PON2) gene expression were increased by OH-dDHL. We showed that the anoI-deletion mutant strains have less intracellular invasion compared to the wild-type strain, and their virulence, such as colonization and dissemination, was decreased in vivo. Consequently, these findings revealed that OH-dDHL, as a virulence factor, contributes to bacterial infection and survival as well as the modification of host responses in the early stages of infection.

scholarly journals Loss of Sirt3 accelerates arterial thrombosis by increasing formation of neutrophil extracellular traps and plasma tissue factor activity

2018 ◽  
Vol 114 (8) ◽  
pp. 1178-1188 ◽  
Author(s):  
Daniel S Gaul ◽  
Julien Weber ◽  
Lambertus J van Tits ◽  
Susanna Sluka ◽  
Lisa Pasterk ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Bone Marrow ◽  
Arterial Thrombosis ◽  
Ex Vivo ◽  
Neutrophil Extracellular Traps ◽  
Wild Type ◽  
Rotational Thromboelastometry ◽  
Extracellular Traps

AbstractAimsSirtuin 3 (Sirt3) is a mitochondrial, nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that reduces oxidative stress by activation of superoxide dismutase 2 (SOD2). Oxidative stress enhances arterial thrombosis. This study investigated the effects of genetic Sirt3 deletion on arterial thrombosis in mice in an inflammatory setting and assessed the clinical relevance of these findings in patients with ST-elevation myocardial infarction (STEMI).Methods and resultsUsing a laser-induced carotid thrombosis model with lipopolysaccharide (LPS) challenge, in vivo time to thrombotic occlusion in Sirt3−/− mice (n = 6) was reduced by half compared to Sirt3+/+ wild-type (n = 8, P < 0.01) controls. Ex vivo analyses of whole blood using rotational thromboelastometry revealed accelerated clot formation and increased clot stability in Sirt3−/− compared to wild-type blood. rotational thromboelastometry of cell-depleted plasma showed accelerated clotting initiation in Sirt3−/− mice, whereas overall clot formation and firmness remained unaffected. Ex vivo LPS-induced neutrophil extracellular trap formation was increased in Sirt3−/− bone marrow-derived neutrophils. Plasma tissue factor (TF) levels and activity were elevated in Sirt3−/− mice, whereas plasma levels of other coagulation factors and TF expression in arterial walls remained unchanged. SOD2 expression in bone marrow -derived Sirt3−/− neutrophils was reduced. In STEMI patients, transcriptional levels of Sirt3 and its target SOD2 were lower in CD14+ leukocytes compared with healthy donors (n = 10 each, P < 0.01).ConclusionsSirt3 loss-of-function enhances experimental thrombosis in vivo via an increase of neutrophil extracellular traps and elevation of TF suggesting thrombo-protective effects of endogenous Sirt3. Acute coronary thrombosis in STEMI patients is associated with lower expression levels of SIRT3 and SOD2 in CD14+ leukocytes. Therefore, enhancing SIRT3 activity by pan-sirtuin activating NAD+-boosters may provide a novel therapeutic target to prevent or treat thrombotic arterial occlusion in myocardial infarction or stroke.

Negative regulation of activated α2 integrins during thrombopoiesis

Blood ◽  
2009 ◽  
Vol 113 (25) ◽  
pp. 6428-6439 ◽  
Author(s):  
Zhiying Zou ◽  
Alec A. Schmaier ◽  
Lan Cheng ◽  
Patricia Mericko ◽  
S. Kent Dickeson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Ex Vivo ◽  
Hematopoietic Cells ◽  
Surface Expression ◽  
Wild Type ◽  
Vessel Injury ◽  
Rapid Signaling ◽  
Α2 Receptors

Abstract Circulating platelets exhibit rapid signaling and adhesive responses to collagen that facilitate hemostasis at sites of vessel injury. Because platelets are anuclear, their collagen receptors must be expressed by megakaryocytes, platelet precursors that arise in the collagen-rich environment of the bone marrow. Whether and how megakaryocytes regulate collagen adhesion during their development in the bone marrow are unknown. We find that surface expression of activated, but not wild-type, α2 integrins in hematopoietic cells in vivo results in the generation of platelets that lack surface α2 receptors. Culture of hematopoietic progenitor cells ex vivo reveals that surface levels of activated, but not wild-type, α2 integrin receptors are rapidly down-regulated during cell growth on collagen but reach wild-type levels when cells are grown in the absence of collagen. Progenitor cells that express activated α2 integrins are normally distributed in the bone marrow in vivo and exhibit normal migration across a collagen-coated membrane ex vivo. This migration is accompanied by rapid down-regulation of activated surface integrins. These studies identify ligand-dependent removal of activated α2 receptors from the cell surface as a mechanism by which integrin function can be negatively regulated in hematopoietic cells during migration between the adhesive environment of the bone marrow and the nonadhesive environment of the circulating blood.

Stat3 Is Required for In Vivo G-CSF-Responsiveness and Neutrophil Function.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 817-817
Author(s):  
Athanasia D. Panopoulos ◽  
Donghoon Yoon ◽  
Ling Zhang ◽  
Stephanie S. Watowich
Keyword(s):  
Bone Marrow ◽  
Actin Polymerization ◽  
Ex Vivo ◽  
Fold Increase ◽  
Peripheral Circulation ◽  
Marrow Transplant ◽  
Wild Type ◽  
Littermate Control ◽  
Hematopoietic Stem

Abstract Granulocyte-colony stimulating factor (G-CSF) and its receptor (G-CSFR) are essential for neutrophil development. The G-CSF/G-CSFR pathway supplies normal circulating neutrophil levels and supports neutrophil terminal maturation. These activities have been exploited clinically, where G-CSF is used frequently to treat congenital or therapeutically induced neutropenia, or to mobilize hematopoietic stem cells for bone marrow transplant. Previous work from our laboratory and others has shown a role for the major G-CSF-responsive signaling molecule STAT3 in granulopoiesis. It is well established that STAT3 has an important negative function in controlling neutrophil production. Importantly, our studies have elucidated a critical positive regulatory role for STAT3 in G-CSF-responsiveness and development of functional neutrophils in vivo. Mice lacking STAT3 in the bone marrow (TIE2cre/Stat3f/Δ) fail to upregulate circulating neutrophil levels in response to a single dose of G-CSF administered subcutaneously, while their wild type littermates demonstrate a two-fold increase in circulating neutrophil levels (e.g., Gr-1+/CD11b+ cells) under these conditions. Inspection of bone marrow responses revealed an increase in the Gr-1lo/CD11bhi population and a corresponding decrease in the Gr-1hi/CD11bhi population of littermate control animals following G-CSF administration. Strikingly, mice that lack functional STAT3 in the bone marrow fail to respond to G-CSF similarly; these animals do not demonstrate an induction in the Gr-1lo/CD11bhi population, or a decrease in the Gr-1hi/CD11bhi population within the bone marrow following G-CSF treatment. These results indicate that in vivo G-CSF administration recruits early progenitors (e.g., Gr-1lo/CD11bhi cells) into the granulocytic lineage while concomitantly decreasing levels of more mature granulocytes (e.g., Gr-1hi/CD11bhi) within the marrow, which are likely mobilized to the peripheral circulation, and suggest an essential role for STAT3 in these responses. Furthermore, neutrophils isolated from TIE2cre/Stat3f/Δ mice demonstrate defective chemotaxis in response to MIP-2. This deficiency appears to be cell autonomous since granulocytes derived from an ex vivo differentiation system show a similar phenotype. Defective chemotaxis may be due in part to improper actin rearrangement dynamics, since STAT3 deficient neutrophils show enhanced actin polymerization in response to MIP-2 compared to wild type controls. To examine potential pathways by which STAT3 may function, we investigated the expression of the PU.1 transcription factor in TIE2cre/Stat3f/Δ mice. PU.1 is known to control expression of genes that are essential for mature neutrophil functions. Our results demonstrate that PU.1 is expressed at high levels in the Gr-1lo/CD11bhi population relative to the Gr-1hi/CD11bhi population isolated from bone marrow of wild type mice. Ex vivo G-CSF treatment of wild type bone marrow stimulates an increase in the proportion of Gr-1lo/CD11bhi cells within the culture, as well as the total PU.1 protein level of the population. By contrast, induction of Gr-1lo/CD11bhi cells and total PU.1 expression by G-CSF treatment ex vivo is abrogated in bone marrow from TIE2cre/Stat3f/Δ mice. Importantly, these effects are not due to significant changes in cell survival or selection in the ex vivo culture system. Collectively, our results indicate that STAT3 is essential for G-CSF-mediated neutrophil responses and function in vivo, and suggest that STAT3-dependent regulation of PU.1 may be an important intermediate in this pathway.

Abstract 341: The Role of Nucleotidase in Arterial Thrombosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Roman Covarrubias ◽  
Elena Chepurko ◽  
Tatiana Novitskaya ◽  
Karen M Dwyer ◽  
Simon C Robson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Carotid Artery ◽  
Ferric Chloride ◽  
Arterial Thrombosis ◽  
Ex Vivo ◽  
Wild Type ◽  
Circulating Cells ◽  
Clodronate Liposome

Objective: To determine how leukocyte nucleotidase affects arterial thrombosis. Approach and Results: Ectonucleoside triphosphate diphosphohydrolase-1 (CD39) is expressed on circulating cells, endothelium and smooth muscle cells where it hydrolyzes extracellular ATP or ADP to AMP. We have demonstrated that transgenic mice with a global overexpression of human CD39 (hCD39-Tg) are protected against ferric chloride-induced carotid artery thrombosis. Furthermore, transplant of hCD39-Tg bone marrow into WT recipient mice increases the time to thrombosis when compared to recipient mice (wild-type or hCD39-Tg) receiving wild-type bone marrow. Based upon these data and previously published work, we hypothesized that CD39 expression on leukocytes is responsible for the prolongation of the time to thrombosis measured in hCD39-Tg mice. To test this hypothesis, we first performed ex vivo mixing experiments. Addition of hCD39-Tg monocytes to WT blood inhibits the expression of activated glycoprotein IIb/IIIa on platelets in response to ADP as measured by FACS analysis (Baseline: 1224 ± 94.9 MFI vs hCD39-Tg monocytes: 663.5 ± 61.5 activated glycoprotein IIb/IIIa MFI: n=4; p< 0.001). Subsequently, in vivo we demonstrated that monocytes with increased CD39 contribute to extending the time to thrombosis. Clodronate liposome depletion of monocytes (WT: 69% decrease; hCD39-Tg: 63% decrease) resulted in a normalization of the time to thrombosis in hCD39-Tg mice (8.0 ± 1.07 minutes, n = 10) when compared to control loaded liposomes (120.0 ± 0.0, n = 14). No changes in the time to thrombosis were detected in wild-type mice treated with clodronate (8.6 ± 1.35 minutes, n = 8) or control liposomes (7.8 ± 0.80 minutes, n=8). Conclusion: Increased expression of CD39 on monocytes can inhibit platelet activation and extend the time to thrombosis following ferric chloride-induced carotid artery injury.

scholarly journals Differential effect of anesthetics on mucociliary clearance in vivo in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kyle S. Feldman ◽  
Eunwon Kim ◽  
Michael J. Czachowski ◽  
Yijen Wu ◽  
Cecilia W. Lo ◽  
...  
Keyword(s):  
Mucociliary Clearance ◽  
Defense Mechanism ◽  
Ex Vivo ◽  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
Wild Type ◽  
Sulfur Colloid ◽  
Ct System

AbstractRespiratory mucociliary clearance (MCC) is a key defense mechanism that functions to entrap and transport inhaled pollutants, particulates, and pathogens away from the lungs. Previous work has identified a number of anesthetics to have cilia depressive effects in vitro. Wild-type C57BL/6 J mice received intra-tracheal installation of 99mTc-Sulfur colloid, and were imaged using a dual-modality SPECT/CT system at 0 and 6 h to measure baseline MCC (n = 8). Mice were challenged for one hour with inhalational 1.5% isoflurane, or intraperitoneal ketamine (100 mg/kg)/xylazine (20 mg/kg), ketamine (0.5 mg/kg)/dexmedetomidine (50 mg/kg), fentanyl (0.2 mg/kg)/1.5% isoflurane, propofol (120 mg/Kg), or fentanyl/midazolam/dexmedetomidine (0.025 mg/kg/2.5 mg/kg/0.25 mg/kg) prior to MCC assessment. The baseline MCC was 6.4%, and was significantly reduced to 3.7% (p = 0.04) and 3.0% (p = 0.01) by ketamine/xylazine and ketamine/dexmedetomidine challenge respectively. Importantly, combinations of drugs containing fentanyl, and propofol in isolation did not significantly depress MCC. Although no change in cilia length or percent ciliation was expected, we tried to correlate ex-vivo tracheal cilia ciliary beat frequency and cilia-generated flow velocities with MCC and found no correlation. Our results indicate that anesthetics containing ketamine (ketamine/xylazine and ketamine/dexmedetomidine) significantly depress MCC, while combinations containing fentanyl (fentanyl/isoflurane, fentanyl/midazolam/dexmedetomidine) and propofol do not. Our method for assessing MCC is reproducible and has utility for studying the effects of other drug combinations.

scholarly journals GPR109A mediates the effects of hippuric acid on regulating osteoclastogenesis and bone resorption in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jin-Ran Chen ◽  
Haijun Zhao ◽  
Umesh D. Wankhade ◽  
Sree V. Chintapalli ◽  
Can Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Mass ◽  
Hippuric Acid ◽  
Ex Vivo ◽  
Marrow Cell ◽  
Osteoclast Differentiation ◽  
Bone Homeostasis ◽  
Wild Type ◽  
Osteoclast Precursors

AbstractThe G protein-coupled receptor 109 A (GPR109A) is robustly expressed in osteoclastic precursor macrophages. Previous studies suggested that GPR109A mediates effects of diet-derived phenolic acids such as hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3-PPA) on promoting bone formation. However, the role of GPR109A in metabolic bone homeostasis and osteoclast differentiation has not been investigated. Using densitometric, bone histologic and molecular signaling analytic methods, we uncovered that bone mass and strength were significantly higher in tibia and spine of standard rodent diet weaned 4-week-old and 6-month-old GPR109A gene deletion (GPR109A−/−) mice, compared to their wild type controls. Osteoclast numbers in bone and in ex vivo bone marrow cell cultures were significantly decreased in GPR109A−/− mice compared to wild type controls. In accordance with these data, CTX-1 in bone marrow plasma and gene expression of bone resorption markers (TNFα, TRAP, Cathepsin K) were significantly decreased in GPR109A−/− mice, while on the other hand, P1NP was increased in serum from both male and female GPR109A−/− mice compared to their respective controls. GPR109A deletion led to suppressed Wnt/β-catenin signaling in osteoclast precursors to inhibit osteoclast differentiation and activity. Indeed, HA and 3-3-PPA substantially inhibited RANKL-induced GPR109A expression and Wnt/β-catenin signaling in osteoclast precursors and osteoclast differentiation. Resultantly, HA significantly inhibited bone resorption and increased bone mass in wild type mice, but had no additional effects on bone in GPR109A−/− mice compared with their respective untreated control mice. These results suggest an important role for GPR109A during osteoclast differentiation and bone resorption mediating effects of HA and 3-3-PPA on inhibiting bone resorption during skeletal development.

Abstract P283: Parkin Mediates Mitophagy in Cardioprotection

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Allen M Andres ◽  
Chengqun Huang ◽  
Eric P Ratliff ◽  
Genaro Hernandez ◽  
Pamela Lee ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Wild Type ◽  
Simulated Ischemia ◽  
Selective Targeting ◽  
Cardioprotective Effects ◽  
Mitochondrial Turnover ◽  
First Time

Autophagy-dependent mitochondrial turnover in response to cellular stress is necessary for maintaining cellular homeostasis. However, the mechanisms that govern the selective targeting of damaged mitochondria are poorly understood. Parkin, an E3 ubiquitin ligase, has been shown to be essential for the selective clearance of damaged mitochondria. Parkin is expressed in the heart, yet its function has not been investigated in the context of cardioprotection. We previously reported that autophagy is required for cardioprotection by ischemic preconditioning (IPC). In the present study, we used simulated ischemia in vitro and IPC in hearts (in vivo and ex vivo) to investigate the role of Parkin in mediating cardioprotection. In HL-1 cells, simulated ischemia induced Parkin translocation to mitochondria and mitochondrial elimination. Mitochondrial loss was blunted in Atg5-deficient cells, revealing the requirement for autophagy in mitochondrial elimination. Consistent with previous reports implicating p62/SQSTM1 in mitophagy, we found that downregulation of p62 attenuated mitophagy and exacerbated cell death in HL-1 cardiomyocytes subjected to simulated ischemia. While wild type mice showed p62 translocation to mitochondria after IPC, Parkin knockout mice exhibited attenuated translocation of p62 to mitochondria. Importantly, ablation of Parkin in mice abolished the cardioprotective effects of IPC. These results reveal for the first time the crucial role of Parkin and mitophagy in cardioprotection.

scholarly journals The interplay of osteogenesis and hematopoiesis

2004 ◽  
Vol 167 (6) ◽  
pp. 1113-1122 ◽  
Author(s):  
Sergei A. Kuznetsov ◽  
Mara Riminucci ◽  
Navid Ziran ◽  
Takeo W. Tsutsui ◽  
Alessandro Corsi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Parathyroid Hormone ◽  
Ex Vivo ◽  
Cell Types ◽  
Heterotopic Bone ◽  
Stromal Compartment ◽  
Marrow Space ◽  
Stromal Tissue

The ontogeny of bone marrow and its stromal compartment, which is generated from skeletal stem/progenitor cells, was investigated in vivo and ex vivo in mice expressing constitutively active parathyroid hormone/parathyroid hormone–related peptide receptor (PTH/PTHrP; caPPR) under the control of the 2.3-kb bone-specific mouse Col1A1 promoter/enhancer. The transgene promoted increased bone formation within prospective marrow space, but delayed the transition from bone to bone marrow during growth, the formation of marrow cavities, and the appearance of stromal cell types such as marrow adipocytes and cells supporting hematopoiesis. This phenotype resolved spontaneously over time, leading to the establishment of marrow containing a greatly reduced number of clonogenic stromal cells. Proliferative osteoprogenitors, but not multipotent skeletal stem cells (mesenchymal stem cells), capable of generating a complete heterotopic bone organ upon in vivo transplantation were assayable in the bone marrow of caPPR mice. Thus, PTH/PTHrP signaling is a major regulator of the ontogeny of the bone marrow and its stromal tissue, and of the skeletal stem cell compartment.

scholarly journals Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4905-4914 ◽  
Author(s):  
Ryan D. Schulteis ◽  
Haiyan Chu ◽  
Xuezhi Dai ◽  
Yuhong Chen ◽  
Brandon Edwards ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Liver Failure ◽  
Autoimmune Diabetes ◽  
Cell Development ◽  
Bb Rat ◽  
Wild Type ◽  
Nkt Cell ◽  
Peripheral T Cells

Abstract The loss of Gimap5 (GTPase of the immune-associated protein 5) gene function is the underlying cause of lymphopenia and autoimmune diabetes in the BioBreeding (BB) rat. The in vivo function of murine gimap5 is largely unknown. We show that selective gene ablation of the mouse gimap5 gene impairs the final intrathymic maturation of CD8 and CD4 T cells and compromises the survival of postthymic CD4 and CD8 cells, replicating findings in the BB rat model. In addition, gimap5 deficiency imposes a block of natural killer (NK)- and NKT-cell differentiation. Development of NK/NKT cells is restored on transfer of gimap5−/− bone marrow into a wild-type environment. Mice lacking gimap5 have a median survival of 15 weeks, exhibit chronic hepatic hematopoiesis, and in later stages show pronounced hepatocyte apoptosis, leading to liver failure. This pathology persists in a Rag2-deficient background in the absence of mature B, T, or NK cells and cannot be adoptively transferred by transplanting gimap5−/− bone marrow into wild-type recipients. We conclude that mouse gimap5 is necessary for the survival of peripheral T cells, NK/NKT-cell development, and the maintenance of normal liver function. These functions involve cell-intrinsic as well as cell-extrinsic mechanisms.

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