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Kinetics of adult hematopoietic stem cell differentiation in vivo
Adult hematopoiesis has been studied in terms of progenitor differentiation potentials, whereas its kinetics in vivo is poorly understood. We combined inducible lineage tracing of endogenous adult hematopoietic stem cells (HSCs) with flow cytometry and single-cell RNA sequencing to characterize early steps of hematopoietic differentiation in the steady-state. Labeled cells, comprising primarily long-term HSCs and some short-term HSCs, produced megakaryocytic lineage progeny within 1 wk in a process that required only two to three cell divisions. Erythroid and myeloid progeny emerged simultaneously by 2 wk and included a pr...
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Upadhaya, S., Sawai, C. M., Papalexi, E., Rashidfarrokhi, A., Jang, G., Chattopadhyay, P., Satija, R., Reizis, B. Tags: Stem Cells & Regeneration, Hematopoiesis Articles Source Type: research

CD49b defines functionally mature Treg cells that survey skin and vascular tissues
Regulatory T (Treg) cells prevent autoimmunity by limiting immune responses and inflammation in the secondary lymphoid organs and nonlymphoid tissues. While unique subsets of Treg cells have been described in some nonlymphoid tissues, their relationship to Treg cells in secondary lymphoid organs and circulation remains unclear. Furthermore, it is possible that Treg cells from similar tissue types share largely similar properties. We have identified a short-lived effector Treg cell subset that expresses the α2 integrin, CD49b, and exhibits a unique tissue distribution, being abundant in peripheral blood, vasculature, ...
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Fan, X., Moltedo, B., Mendoza, A., Davydov, A. N., Faire, M. B., Mazutis, L., Sharma, R., Peer, D., Chudakov, D. M., Rudensky, A. Y. Tags: Autoimmunity Articles Source Type: research

Neutrophils instruct homeostatic and pathological states in naive tissues
Immune protection relies on the capacity of neutrophils to infiltrate challenged tissues. Naive tissues, in contrast, are believed to remain free of these cells and protected from their toxic cargo. Here, we show that neutrophils are endowed with the capacity to infiltrate multiple tissues in the steady-state, a process that follows tissue-specific dynamics. By focusing in two particular tissues, the intestine and the lungs, we find that neutrophils infiltrating the intestine are engulfed by resident macrophages, resulting in repression of Il23 transcription, reduced G-CSF in plasma, and reinforced activity of distant bone...
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Casanova-Acebes, M., Nicolas-Avila, J. A., Li, J. L., Garcia-Silva, S., Balachander, A., Rubio-Ponce, A., Weiss, L. A., Adrover, J. M., Burrows, K., A-Gonzalez, N., Ballesteros, I., Devi, S., Quintana, J. A., Crainiciuc, G., Leiva, M., Gunzer, M., Weber, Tags: Innate Immunity and Inflammation Articles Source Type: research

Multiple roles of lymphatic vessels in peripheral lymph node development
The mammalian lymphatic system consists of strategically located lymph nodes (LNs) embedded into a lymphatic vascular network. Mechanisms underlying development of this highly organized system are not fully understood. Using high-resolution imaging, we show that lymphoid tissue inducer (LTi) cells initially transmigrate from veins at LN development sites using gaps in venous mural coverage. This process is independent of lymphatic vasculature, but lymphatic vessels are indispensable for the transport of LTi cells that egress from blood capillaries elsewhere and serve as an essential LN expansion reservoir. At later stages,...
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Bovay, E., Sabine, A., Prat-Luri, B., Kim, S., Son, K., Willrodt, A.-H., Olsson, C., Halin, C., Kiefer, F., Betsholtz, C., Jeon, N. L., Luther, S. A., Petrova, T. V. Tags: Cardiovascular Biology Articles Source Type: research

A20-binding inhibitor of NF-{kappa}B (ABIN) 2 negatively regulates allergic airway inflammation
TPL-2 MAP 3-kinase promotes inflammation in numerous mouse disease models and is an attractive anti-inflammatory drug target. However, TPL-2–deficient (Map3k8–/–) mice develop exacerbated allergic airway inflammation to house dust mite (HDM) compared with wild type controls. Here, we show that Map3k8D270A/D270A mice expressing kinase dead TPL-2 had an unaltered response to HDM, indicating that the severe airway inflammation observed in Map3k8–/– mice is not due to blockade of TPL-2 signaling and rather reflects a TPL-2 adaptor function. Severe allergic inflammation in TPL-2–deficient mic...
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Ventura, S., Cano, F., Kannan, Y., Breyer, F., Pattison, M. J., Wilson, M. S., Ley, S. C. Tags: Innate Immunity and Inflammation Brief Definitive Reports Source Type: research

Human monocytes and macrophages regulate immune tolerance via integrin {alpha}v{beta}8-mediated TGF{beta} activation
Monocytes are crucial immune cells involved in regulation of inflammation either directly or via differentiation into macrophages in tissues. However, many aspects of how their function is controlled in health and disease are not understood. Here we show that human blood monocytes activate high levels of the cytokine TGFβ, a pathway that is not evident in mouse monocytes. Human CD14+, but not CD16+, monocytes activate TGFβ via expression of the integrin αvβ8 and matrix metalloproteinase 14, which dampens their production of TNFα in response to LPS. Additionally, when monocytes differentiate into ...
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Kelly, A., Gunaltay, S., McEntee, C. P., Shuttleworth, E. E., Smedley, C., Houston, S. A., Fenton, T. M., Levison, S., Mann, E. R., Travis, M. A. Tags: Innate Immunity and Inflammation, Mucosal Immunology Brief Definitive Reports Source Type: research

Gain-of-function IKBKB mutation causes human combined immune deficiency
Genetic mutations account for many devastating early onset immune deficiencies. In contrast, less severe and later onset immune diseases, including in patients with no prior family history, remain poorly understood. Whole exome sequencing in two cohorts of such patients identified a novel heterozygous de novo IKBKB missense mutation (c.607G>A) in two separate kindreds in whom probands presented with immune dysregulation, combined T and B cell deficiency, inflammation, and epithelial defects. IKBKB encodes IKK2, which activates NF-B signaling. IKK2V203I results in enhanced NF-B signaling, as well as T and B cell function...
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Cardinez, C., Miraghazadeh, B., Tanita, K., da Silva, E., Hoshino, A., Okada, S., Chand, R., Asano, T., Tsumura, M., Yoshida, K., Ohnishi, H., Kato, Z., Yamazaki, M., Okuno, Y., Miyano, S., Kojima, S., Ogawa, S., Andrews, T. D., Field, M. A., Burgio, G., Tags: Immunodeficiency, Human Disease Genetics Brief Definitive Reports Source Type: research

Transient T-bet expression functionally specifies a distinct T follicular helper subset
T follicular helper (Tfh) cells express transcription factor BCL-6 and cytokine IL-21. Mature Tfh cells are also capable of producing IFN- without expressing the Th1 transcription factor T-bet. Whether this IFN-–producing Tfh population represents a unique Tfh subset with a distinct differentiation pathway is poorly understood. By using T-bet fate–mapping mouse strains, we discovered that almost all the IFN-–producing Tfh cells have previously expressed T-bet and express high levels of NKG2D. DNase I hypersensitivity analysis indicated that the Ifng gene locus is partially accessible in this "ex–T-b...
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Fang, D., Cui, K., Mao, K., Hu, G., Li, R., Zheng, M., Riteau, N., Reiner, S. L., Sher, A., Zhao, K., Zhu, J. Tags: Brief Definitive Reports Source Type: research

Lymph nodes go with the flow
In this issue, Bovay et al. (https://doi.org/10.1084/jem.20180217) invoke a compelling model of interplay between the venous and lymphatic vasculature in regulating the developmental genesis and early expansion of LNs. This work supports an emerging model that lymph–venous crosstalk supports LN functionality at all stages. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Czepielewski, R. S., Randolph, G. J. Tags: Insights Source Type: research

T-bet in Tfh cells: Now you see me, now you dont
In this issue, Fang et al. (https://doi.org/10.1084/jem.20180927) report on a subset of T follicular helper (Tfh) cells that transiently expresses T-bet yet continues to produce IFN- at late stages of GC reactions following immunization. They find other genes uniquely expressed in this IFN-–producing Tfh subset, such as NKG2D, that can be used to better distinguish these functionally distinct Tfh cells. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - November 5, 2018 Category: Internal Medicine Authors: Kaech, S. M. Tags: Insights Source Type: research

Zebrafish blastomere screen identifies retinoic acid suppression of MYB in adenoid cystic carcinoma
Pluripotent cells have been used to probe developmental pathways that are involved in genetic diseases and oncogenic events. To find new therapies that would target MYB-driven tumors, we developed a pluripotent zebrafish blastomere culture system. We performed a chemical genetic screen and identified retinoic acid agonists as suppressors of c-myb expression. Retinoic acid treatment also decreased c-myb gene expression in human leukemia cells. Translocations that drive overexpression of the oncogenic transcription factor MYB are molecular hallmarks of adenoid cystic carcinoma (ACC), a malignant salivary gland tumor with no ...
Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Mandelbaum, J., Shestopalov, I. A., Henderson, R. E., Chau, N. G., Knoechel, B., Wick, M. J., Zon, L. I. Tags: Solid Tumors Articles Source Type: research

Piezo1 and Gq/G11 promote endothelial inflammation depending on flow pattern and integrin activation
The vascular endothelium is constantly exposed to mechanical forces, including fluid shear stress exerted by the flowing blood. Endothelial cells can sense different flow patterns and convert the mechanical signal of laminar flow into atheroprotective signals, including eNOS activation, whereas disturbed flow in atheroprone areas induces inflammatory signaling, including NF-B activation. How endothelial cells distinguish different flow patterns is poorly understood. Here we show that both laminar and disturbed flow activate the same initial pathway involving the mechanosensitive cation channel Piezo1, the purinergic P2Y2 r...
Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Albarran-Juarez, J., Iring, A., Wang, S., Joseph, S., Grimm, M., Strilic, B., Wettschureck, N., Althoff, T. F., Offermanns, S. Tags: Cardiovascular Biology Articles Source Type: research

Remote ischemic post-conditioning promotes hematoma resolution via AMPK-dependent immune regulation
Spontaneous intracerebral hemorrhage (ICH) produces the highest acute mortality and worst outcomes of all stroke subtypes. Hematoma volume is an independent determinant of ICH patient outcomes, making clot resolution a primary goal of clinical management. Herein, remote-limb ischemic post-conditioning (RIC), the repetitive inflation–deflation of a blood pressure cuff on a limb, accelerated hematoma resolution and improved neurological outcomes after ICH in mice. Parabiosis studies revealed RIC accelerated clot resolution via a humoral-mediated mechanism. Whereas RIC increased anti-inflammatory macrophage activation, ...
Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Vaibhav, K., Braun, M., Khan, M. B., Fatima, S., Saad, N., Shankar, A., Khan, Z. T., Harris, R. B. S., Yang, Q., Huo, Y., Arbab, A. S., Giri, S., Alleyne, C. H., Vender, J. R., Hess, D. C., Baban, B., Hoda, M. N., Dhandapani, K. M. Tags: Neuroinflammation, Innate Immunity and Inflammation, Neuroscience Articles Source Type: research

Rapid CLIP dissociation from MHC II promotes an unusual antigen presentation pathway in autoimmunity
A number of autoimmunity-associated MHC class II proteins interact only weakly with the invariant chain–derived class II–associated invariant chain peptide (CLIP). CLIP dissociates rapidly from I-Ag7 even in the absence of DM, and this property is related to the type 1 diabetes–associated β57 polymorphism. We generated knock-in non-obese diabetic (NOD) mice with a single amino acid change in the CLIP segment of the invariant chain in order to moderately slow CLIP dissociation from I-Ag7. These knock-in mice had a significantly reduced incidence of spontaneous type 1 diabetes and diminished islet infi...
Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Ito, Y., Ashenberg, O., Pyrdol, J., Luoma, A. M., Rozenblatt-Rosen, O., Hofree, M., Christian, E., Ferrari de Andrade, L., Tay, R. E., Teyton, L., Regev, A., Dougan, S. K., Wucherpfennig, K. W. Tags: Autoimmunity Articles Source Type: research

N-glycanase NGLY1 regulates mitochondrial homeostasis and inflammation through NRF1
Mutations in the NGLY1 (N-glycanase 1) gene, encoding an evolutionarily conserved deglycosylation enzyme, are associated with a rare congenital disorder leading to global developmental delay and neurological abnormalities. The molecular mechanism of the NGLY1 disease and its function in tissue and immune homeostasis remain unknown. Here, we find that NGLY1-deficient human and mouse cells chronically activate cytosolic nucleic acid–sensing pathways, leading to elevated interferon gene signature. We also find that cellular clearance of damaged mitochondria by mitophagy is impaired in the absence of NGLY1, resulting in ...
Source: The Journal of Experimental Medicine - October 1, 2018 Category: Internal Medicine Authors: Yang, K., Huang, R., Fujihira, H., Suzuki, T., Yan, N. Tags: Innate Immunity and Inflammation, Human Disease Genetics Articles Source Type: research