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Journal of Experimental Medicine

Uzodinma U Uche, Ann R Piccirillo, Shunsuke Kataoka, Stephanie J Grebinoski, Louise M D'Cruz, Lawrence P Kane
Phosphatidylinositol-3 kinases (PI3Ks) modulate cellular growth, proliferation, and survival; dysregulation of the PI3K pathway can lead to autoimmune disease and cancer. PIK3IP1 (or transmembrane inhibitor of PI3K [TrIP]) is a putative transmembrane regulator of PI3K. TrIP contains an extracellular kringle domain and an intracellular domain with homology to the inter-SH2 domain of the PI3K regulatory subunit p85, but the mechanism of TrIP function is poorly understood. We show that both the kringle and p85-like domains are necessary for TrIP inhibition of PI3K and that TrIP is down-modulated from the surface of T cells during T cell activation...
November 14, 2018: Journal of Experimental Medicine
Guilhem R Thierry, Mirela Kuka, Marco De Giovanni, Isabelle Mondor, Nicolas Brouilly, Matteo Iannacone, Marc Bajénoff
Immunoglobulin M (IgM) is the first type of antibody produced during acute infections and thus provides an early line of specific defense against pathogens. Being produced in secondary lymphoid organs, IgM must rapidly be exported to the blood circulation. However, it is currently unknown how such large pentameric molecules are released from lymph nodes (LNs). Here, we show that upon immunization, IgM transiently gains access to the luminal side of the conduit system, a reticular infrastructure enabling fast delivery of tissue-derived soluble substances to the LN parenchyma...
November 14, 2018: Journal of Experimental Medicine
Kieran D James, Emilie J Cosway, Beth Lucas, Andrea J White, Sonia M Parnell, Manuela Carvalho-Gaspar, Alexei V Tumanov, Graham Anderson, William E Jenkinson
The emigration of mature thymocytes from the thymus is critical for establishing peripheral T cell compartments. However, the pathways controlling this process and the timing of egress in relation to postselection developmental stages are poorly defined. Here, we reexamine thymocyte egress and test current and opposing models in relation to the requirement for LTβR, a regulator of thymic microenvironments and thymocyte emigration. Using cell-specific gene targeting, we show that the requirement for LTβR in thymocyte egress is distinct from its control of thymic epithelium and instead maps to expression by endothelial cells...
November 13, 2018: Journal of Experimental Medicine
Rebecca Gentek, Clément Ghigo, Guillaume Hoeffel, Audrey Jorquera, Rasha Msallam, Stephan Wienert, Frederick Klauschen, Florent Ginhoux, Marc Bajénoff
The murine epidermis harbors two immune cell lineages, Langerhans cells (LCs) and γδ T cells known as dendritic epidermal T cells (DETCs). LCs develop from both early yolk sac (YS) progenitors and fetal liver monocytes before locally self-renewing in the adult. For DETCs, the mechanisms of homeostatic maintenance and their hematopoietic origin are largely unknown. Here, we exploited multicolor fate mapping systems to reveal that DETCs slowly turn over at steady state. Like for LCs, homeostatic maintenance of DETCs is achieved by clonal expansion of tissue-resident cells assembled in proliferative units...
November 8, 2018: Journal of Experimental Medicine
Ingrid M Ariës, Kimberly Bodaar, Salmaan A Karim, Triona Ni Chonghaile, Laura Hinze, Melissa A Burns, Maren Pfirrmann, James Degar, Jack T Landrigan, Sebastian Balbach, Sofie Peirs, Björn Menten, Randi Isenhart, Kristen E Stevenson, Donna S Neuberg, Meenakshi Devidas, Mignon L Loh, Stephen P Hunger, David T Teachey, Karen R Rabin, Stuart S Winter, Kimberly P Dunsmore, Brent L Wood, Lewis B Silverman, Stephen E Sallan, Pieter Van Vlierberghe, Stuart H Orkin, Birgit Knoechel, Anthony G Letai, Alejandro Gutierrez
The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondrial apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components ( EZH2 , EED , or SUZ12 ) were associated with mitochondrial apoptosis resistance...
November 7, 2018: Journal of Experimental Medicine
Reem Abdel-Haq, Johannes C M Schlachetzki, Christopher K Glass, Sarkis K Mazmanian
Microglia, the resident immune cells in the brain, are essential for modulating neurogenesis, influencing synaptic remodeling, and regulating neuroinflammation by surveying the brain microenvironment. Microglial dysfunction has been implicated in the onset and progression of several neurodevelopmental and neurodegenerative diseases; however, the multitude of factors and signals influencing microglial activity have not been fully elucidated. Microglia not only respond to local signals within the brain but also receive input from the periphery, including the gastrointestinal (GI) tract...
November 1, 2018: Journal of Experimental Medicine
Ryan S Lane, Julia Femel, Alec P Breazeale, Christopher P Loo, Guillaume Thibault, Andy Kaempf, Motomi Mori, Takahiro Tsujikawa, Young Hwan Chang, Amanda W Lund
Mechanisms of immune suppression in peripheral tissues counteract protective immunity to prevent immunopathology and are coopted by tumors for immune evasion. While lymphatic vessels facilitate T cell priming, they also exert immune suppressive effects in lymph nodes at steady-state. Therefore, we hypothesized that peripheral lymphatic vessels acquire suppressive mechanisms to limit local effector CD8+ T cell accumulation in murine skin. We demonstrate that nonhematopoietic PD-L1 is largely expressed by lymphatic and blood endothelial cells and limits CD8+ T cell accumulation in tumor microenvironments...
October 31, 2018: Journal of Experimental Medicine
Zhi-Hao Wang, Pai Liu, Xia Liu, Shan Ping Yu, Jian-Zhi Wang, Keqiang Ye
SRPK2 is abnormally activated in tauopathies including Alzheimer's disease (AD). SRPK2 is known to play an important role in pre-mRNA splicing by phosphorylating SR-splicing factors. Dysregulation of tau exon 10 pre-mRNA splicing causes pathological imbalances in 3R- and 4R-tau, leading to neurodegeneration; however, the role of SRPK2 in these processes remains unclear. Here we show that delta-secretase (also known as asparagine endopeptidase; AEP), which is activated in AD, cleaves SRPK2 and increases its nuclear translocation as well as kinase activity, augmenting exon 10 inclusion...
October 29, 2018: Journal of Experimental Medicine
Juliana Durack, Susan V Lynch
Over the past decade, our view of human-associated microbes has expanded beyond that of a few species toward an appreciation of the diverse and niche-specialized microbial communities that develop in the human host with chronological age. The largest reservoir of microbes exists in the distal gastrointestinal tract, both in the lumen, where microbes facilitate primary and secondary metabolism, and on mucosal surfaces, where they interact with host immune cell populations. While local microbial-driven immunomodulation in the gut is well described, more recent studies have demonstrated a role for the gut microbiome in influencing remote organs and mucosal and hematopoietic immune function...
October 15, 2018: Journal of Experimental Medicine
James W Keith, Eric G Pamer
The emergence of antibiotic-resistant bacterial pathogens is an all-too-common consequence of antibiotic use. Although antibiotic resistance among virulent bacterial pathogens is a growing concern, the highest levels of antibiotic resistance occur among less pathogenic but more common bacteria that are prevalent in healthcare settings. Patient-to-patient transmission of these antibiotic-resistant bacteria is a perpetual concern in hospitals. Many of these resistant microbes, such as vancomycin-resistant Enterococcus faecium and carbapenem-resistant Klebsiella pneumoniae , emerge from the intestinal lumen and invade the bloodstream of vulnerable patients, causing disseminated infection...
October 11, 2018: Journal of Experimental Medicine
Rafael S Czepielewski, Gwendalyn J Randolph
In this issue, Bovay et al. ( 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.
November 5, 2018: Journal of Experimental Medicine
Xiying Fan, Bruno Moltedo, Alejandra Mendoza, Alexey N Davydov, Mehlika B Faire, Linas Mazutis, Roshan Sharma, Dana Pe'er, Dmitriy M Chudakov, Alexander Y Rudensky
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, skin, and skin-draining lymph nodes, but uncommon in the intestines and in viscera-draining lymph nodes...
November 5, 2018: Journal of Experimental Medicine
Olivier Disson, Camille Blériot, Jean-Marie Jacob, Nicolas Serafini, Sophie Dulauroy, Grégory Jouvion, Cindy Fevre, Grégoire Gessain, Pierre Thouvenot, Gérard Eberl, James P Di Santo, Lucie Peduto, Marc Lecuit
The foodborne pathogen Listeria monocytogenes ( Lm ) crosses the intestinal villus epithelium via goblet cells (GCs) upon the interaction of Lm surface protein InlA with its receptor E-cadherin. Here, we show that Lm infection accelerates intestinal villus epithelium renewal while decreasing the number of GCs expressing luminally accessible E-cadherin, thereby locking Lm portal of entry. This novel innate immune response to an enteropathogen is triggered by the infection of Peyer's patch CX3CR1+ cells and the ensuing production of IL-23...
November 5, 2018: Journal of Experimental Medicine
Esther Bovay, Amélie Sabine, Borja Prat-Luri, Sudong Kim, Kyungmin Son, Ann-Helen Willrodt, Cecilia Olsson, Cornelia Halin, Friedemann Kiefer, Christer Betsholtz, Noo Li Jeon, Sanjiv A Luther, Tatiana V Petrova
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...
November 5, 2018: Journal of Experimental Medicine
Aoife Kelly, Sezin Gunaltay, Craig P McEntee, Elinor E Shuttleworth, Catherine Smedley, Stephanie A Houston, Thomas M Fenton, Scott Levison, Elizabeth R Mann, Mark A Travis
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...
November 5, 2018: Journal of Experimental Medicine
Chelisa Cardinez, Bahar Miraghazadeh, Kay Tanita, Elizabeth da Silva, Akihiro Hoshino, Satoshi Okada, Rochna Chand, Takaki Asano, Miyuki Tsumura, Kenichi Yoshida, Hidenori Ohnishi, Zenichiro Kato, Masahide Yamazaki, Yusuke Okuno, Satoru Miyano, Seiji Kojima, Seishi Ogawa, T Daniel Andrews, Matthew A Field, Gaetan Burgio, Tomohiro Morio, Carola G Vinuesa, Hirokazu Kanegane, Matthew C Cook
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-κB signaling...
November 5, 2018: Journal of Experimental Medicine
Sonia Ventura, Florencia Cano, Yashaswini Kannan, Felix Breyer, Michael J Pattison, Mark S Wilson, Steven C Ley
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...
November 5, 2018: Journal of Experimental Medicine
Yong Cheng, Jeffrey S Schorey
RNA sensing pathways are key elements in a host immune response to viral pathogens, but little is known of their importance during bacterial infections. We found that Mycobacterium tuberculosis ( M.tb ) actively releases RNA into the macrophage cytosol using the mycobacterial SecA2 and ESX-1 secretion systems. The cytosolic M.tb RNA induces IFN-β production through the host RIG-I/MAVS/IRF7 RNA sensing pathway. The inducible expression of IRF7 within infected cells requires an autocrine signaling through IFN-β and its receptor, and this early IFN-β production is dependent on STING and IRF3 activation...
November 5, 2018: Journal of Experimental Medicine
Susan M Kaech
In this issue, Fang et al. ( report on a subset of T follicular helper (Tfh) cells that transiently expresses T-bet yet continues to produce IFN-γ at late stages of GC reactions following immunization. They find other genes uniquely expressed in this IFN-γ-producing Tfh subset, such as NKG2D, that can be used to better distinguish these functionally distinct Tfh cells.
November 5, 2018: Journal of Experimental Medicine
Maria Buxadé, Hector Huerga Encabo, Marta Riera-Borrull, Lucía Quintana-Gallardo, Pilar López-Cotarelo, Mónica Tellechea, Sara Martínez-Martínez, Juan Miguel Redondo, Juan Martín-Caballero, Juana María Flores, Elena Bosch, José Luis Rodríguez-Fernández, Jose Aramburu, Cristina López-Rodríguez
MHCII in antigen-presenting cells (APCs) is a key regulator of adaptive immune responses. Expression of MHCII genes is controlled by the transcription coactivator CIITA, itself regulated through cell type-specific promoters. Here we show that the transcription factor NFAT5 is needed for expression of Ciita and MHCII in macrophages, but not in dendritic cells and other APCs. NFAT5-deficient macrophages showed defective activation of MHCII-dependent responses in CD4+ T lymphocytes and attenuated capacity to elicit graft rejection in vivo...
November 5, 2018: Journal of Experimental Medicine
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