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Naomi A Yudanin, Frederike Schmitz, Anne-Laure Flamar, Joseph J C Thome, Elia Tait Wojno, Jesper B Moeller, Melanie Schirmer, Isabel J Latorre, Ramnik J Xavier, Donna L Farber, Laurel A Monticelli, David Artis
Innate lymphoid cells (ILC) play critical roles in regulating immunity, inflammation, and tissue homeostasis in mice. However, limited access to non-diseased human tissues has hindered efforts to profile anatomically-distinct ILCs in humans. Through flow cytometric and transcriptional analyses of lymphoid, mucosal, and metabolic tissues from previously healthy human organ donors, here we have provided a map of human ILC heterogeneity across multiple anatomical sites. In contrast to mice, human ILCs are less strictly compartmentalized and tissue localization selectively impacts ILC distribution in a subset-dependent manner...
February 11, 2019: Immunity
Carlos M Minutti, Rucha V Modak, Felicity Macdonald, Fengqi Li, Danielle J Smyth, David A Dorward, Natalie Blair, Connor Husovsky, Andrew Muir, Evangelos Giampazolias, Ross Dobie, Rick M Maizels, Timothy J Kendall, David W Griggs, Manfred Kopf, Neil C Henderson, Dietmar M Zaiss
The epidermal growth factor receptor ligand Amphiregulin has a well-documented role in the restoration of tissue homeostasis after injury; however, the mechanism by which Amphiregulin contributes to wound repair remains unknown. Here we show that Amphiregulin functioned by releasing bioactive transforming growth factor beta (TGF-β) from latent complexes via integrin-αV activation. Using acute injury models in two different tissues, we found that by inducing TGF-β activation on mesenchymal stromal cells (pericytes), Amphiregulin induced their differentiation into myofibroblasts, thereby selectively contributing to the restoration of vascular barrier function within injured tissue...
February 6, 2019: Immunity
Fanghui Zhang, Rongrong Li, Yunshan Yang, Chunhui Shi, Yingying Shen, Chaojie Lu, Yinghu Chen, Wu Zhou, Aifu Lin, Lei Yu, Wanjing Zhang, Zhenwei Xue, Jianli Wang, Zhijian Cai
Systemic immunosuppression greatly affects the chemotherapeutic antitumor effect. Here, we showed that CD19+ extracellular vesicles (EVs) from B cells through CD39 and CD73 vesicle-incorporated proteins hydrolyzed ATP from chemotherapy-treated tumor cells into adenosine, thus impairing CD8+ T cell responses. Serum CD19+ EVs were increased in tumor-bearing mice and patients. Patients with fewer serum CD19+ EVs had a better prognosis after chemotherapy. Upregulated hypoxia-inducible factor-1α (HIF-1α) promoted B cells to release CD19+ EVs by inducing Rab27a mRNA transcription...
February 6, 2019: Immunity
Hitesh Arora, Sara Morgan Wilcox, Laura Alexandra Johnson, Lonna Munro, Brett Alexander Eyford, Cheryl Gurine Pfeifer, Ian Welch, Wilfred Arthur Jefferies
Sepsis is a bi-phasic inflammatory disease that threatens approximately 30 million lives and claims over 14 million annually, yet little is known regarding the molecular switches and pathways that regulate this disease. Here, we have described ABCF1, an ATP-Binding Cassette (ABC) family member protein, which possesses an E2 ubiquitin enzyme activity, through which it controls the Lipopolysaccharide (LPS)- Toll-like Receptor-4 (TLR4) mediated gram-negative insult by targeting key proteins for K63-polyubiquitination...
February 6, 2019: Immunity
Xinghui Li, Wei Gong, Hao Wang, Tianliang Li, Kuldeep S Attri, Robert E Lewis, Andre C Kalil, Fatema Bhinderwala, Robert Powers, Guowei Yin, Laura E Herring, John M Asara, Yu L Lei, Xiaoyong Yang, Diego A Rodriguez, Mao Yang, Douglas R Green, Pankaj K Singh, Haitao Wen
Elevated glucose metabolism in immune cells represents a hallmark feature of many inflammatory diseases, such as sepsis. However, the role of individual glucose metabolic pathways during immune cell activation and inflammation remains incompletely understood. Here, we demonstrate a previously unrecognized anti-inflammatory function of the O-linked β-N-acetylglucosamine (O-GlcNAc) signaling associated with the hexosamine biosynthesis pathway (HBP). Despite elevated activities of glycolysis and the pentose phosphate pathway, activation of macrophages with lipopolysaccharide (LPS) resulted in attenuated HBP activity and protein O-GlcNAcylation...
February 5, 2019: Immunity
Renée R C E Schreurs, Martin E Baumdick, Adrian F Sagebiel, Max Kaufmann, Michal Mokry, Paul L Klarenbeek, Nicola Schaltenberg, Fenja L Steinert, Jorik M van Rijn, Agata Drewniak, Sarah-May M L The, Roel Bakx, Joep P M Derikx, Niek de Vries, Willemijn E Corpeleijn, Steven T Pals, Nicola Gagliani, Manuel A Friese, Sabine Middendorp, Edward E S Nieuwenhuis, Konrad Reinshagen, Teunis B H Geijtenbeek, Johannes B van Goudoever, Madeleine J Bunders
Although the fetal immune system is considered tolerogenic, preterm infants can suffer from severe intestinal inflammation, including necrotizing enterocolitis (NEC). Here, we demonstrate that human fetal intestines predominantly contain tumor necrosis factor-α (TNF-α)+ CD4+ CD69+ T effector memory (Tem) cells. Single-cell RNA sequencing of fetal intestinal CD4+ T cells showed a T helper 1 phenotype and expression of genes mediating epithelial growth and cell cycling. Organoid co-cultures revealed a dose-dependent, TNF-α-mediated effect of fetal intestinal CD4+ T cells on intestinal stem cell (ISC) development, in which low T cell numbers supported epithelial development, whereas high numbers abrogated ISC proliferation...
February 5, 2019: Immunity
Chien-Chun Steven Pai, John T Huang, Xiaoqing Lu, Donald M Simons, Chanhyuk Park, Anthony Chang, Whitney Tamaki, Eric Liu, Kole T Roybal, Jane Seagal, Mingyi Chen, Katsunobu Hagihara, Xiao X Wei, Michel DuPage, Serena S Kwek, David Y Oh, Adil Daud, Katy K Tsai, Clint Wu, Li Zhang, Marcella Fasso, Ravi Sachidanandam, Anitha Jayaprakash, Ingrid Lin, Amy-Jo Casbon, Gillian A Kinsbury, Lawrence Fong
Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes...
February 1, 2019: Immunity
Véronique Adoue, Bénédicte Binet, Agathe Malbec, Joanna Fourquet, Paola Romagnoli, Joost P M van Meerwijk, Sebastian Amigorena, Olivier P Joffre
Upon activation, naive CD4+ T cells differentiate into distinct T cell subsets via processes reliant on epigenetically regulated, lineage-specific developmental programs. Here, we examined the function of the histone methyltransferase SETDB1 in T helper (Th) cell differentiation. Setdb1-/- naive CD4+ T cells exhibited exacerbated Th1 priming, and when exposed to a Th1-instructive signal, Setdb1-/- Th2 cells crossed lineage boundaries and acquired a Th1 phenotype. SETDB1 did not directly control Th1 gene promoter activity but relied instead on deposition of the repressive H3K9me3 mark at a restricted and cell-type-specific set of endogenous retroviruses (ERVs) located in the vicinity of genes involved in immune processes...
January 31, 2019: Immunity
Julia A Brown, Gursewak Singh, Joshua A Acklin, Silviana Lee, James E Duehr, Anupa N Chokola, Justin J Frere, Kevin W Hoffman, Gregory A Foster, David Krysztof, Richard Cadagan, Adam R Jacobs, Susan L Stramer, Florian Krammer, Adolfo García-Sastre, Jean K Lim
Zika virus (ZIKV) has recently been associated with birth defects and pregnancy loss after maternal infection. Because dengue virus (DENV) and ZIKV co-circulate, understanding the role of antibody-dependent enhancement in the context of pregnancy is critical. Here, we showed that the presence of DENV-specific antibodies in ZIKV-infected pregnant mice significantly increased placental damage, fetal growth restriction, and fetal resorption. This was associated with enhanced viral replication in the placenta that coincided with an increased frequency of infected trophoblasts...
January 30, 2019: Immunity
Jing Zhou, Hui Peng, Kun Li, Kun Qu, Baohui Wang, Yuzhang Wu, Lilin Ye, Zhongjun Dong, Haiming Wei, Rui Sun, Zhigang Tian
The tolerogenic microenvironment of the liver is associated with impaired hepatic T cell function. Here, we examined the contribution of liver-resident natural killer (LrNK) cells, a prominent hepatic NK cell compartment, to T cell antiviral responses in the liver. The number of virus-specific T cells increased in LrNK-cell-deficient mice during both acute and chronic lymphocytic choriomeningitis virus infection. Upon infection with adenovirus, hepatic T cells from these mice produced more cytokines, which was accompanied by reduced viral loads...
January 24, 2019: Immunity
Louise V Webb, Alessandro Barbarulo, Jelle Huysentruyt, Tom Vanden Berghe, Nozomi Takahashi, Steven Ley, Peter Vandenabeele, Benedict Seddon
NF-κB (nuclear factor κB) signaling is considered critical for single positive (SP) thymocyte development because loss of upstream activators of NF-κB, such as the IKK complex, arrests their development. We found that the compound ablation of RelA, cRel, and p50, required for canonical NF-κB transcription, had no impact upon thymocyte development. While IKK-deficient thymocytes were acutely sensitive to tumor necrosis factor (TNF)-induced cell death, Rel-deficient cells remained resistant, calling into question the importance of NF-κB as the IKK target required for thymocyte survival...
January 23, 2019: Immunity
Ricardo J Miragaia, Tomás Gomes, Agnieszka Chomka, Laura Jardine, Angela Riedel, Ahmed N Hegazy, Natasha Whibley, Andrea Tucci, Xi Chen, Ida Lindeman, Guy Emerton, Thomas Krausgruber, Jacqueline Shields, Muzlifah Haniffa, Fiona Powrie, Sarah A Teichmann
Non-lymphoid tissues (NLTs) harbor a pool of adaptive immune cells with largely unexplored phenotype and development. We used single-cell RNA-seq to characterize 35,000 CD4+ regulatory (Treg) and memory (Tmem) T cells in mouse skin and colon, their respective draining lymph nodes (LNs) and spleen. In these tissues, we identified Treg cell subpopulations with distinct degrees of NLT phenotype. Subpopulation pseudotime ordering and gene kinetics were consistent in recruitment to skin and colon, yet the initial NLT-priming in LNs and the final stages of NLT functional adaptation reflected tissue-specific differences...
January 23, 2019: Immunity
Julie Schulthess, Sumeet Pandey, Melania Capitani, Kevin C Rue-Albrecht, Isabelle Arnold, Fanny Franchini, Agnieszka Chomka, Nicholas E Ilott, Daniel G W Johnston, Elisabete Pires, James McCullagh, Stephen N Sansom, Carolina V Arancibia-Cárcamo, Holm H Uhlig, Fiona Powrie
Host microbial cross-talk is essential to maintain intestinal homeostasis. However, maladaptation of this response through microbial dysbiosis or defective host defense toward invasive intestinal bacteria can result in chronic inflammation. We have shown that macrophages differentiated in the presence of the bacterial metabolite butyrate display enhanced antimicrobial activity. Butyrate-induced antimicrobial activity was associated with a shift in macrophage metabolism, a reduction in mTOR kinase activity, increased LC3-associated host defense and anti-microbial peptide production in the absence of an increased inflammatory cytokine response...
January 22, 2019: Immunity
María Martínez-López, Salvador Iborra, Ruth Conde-Garrosa, Annalaura Mastrangelo, Camille Danne, Elizabeth R Mann, Delyth M Reid, Valérie Gaboriau-Routhiau, Maria Chaparro, María P Lorenzo, Lara Minnerup, Paula Saz-Leal, Emma Slack, Benjamin Kemp, Javier P Gisbert, Andrzej Dzionek, Matthew J Robinson, Francisco J Rupérez, Nadine Cerf-Bensussan, Gordon D Brown, David Bernardo, Salomé LeibundGut-Landmann, David Sancho
Production of interleukin-17 (IL-17) and IL-22 by T helper 17 (Th17) cells and group 3 innate lymphoid cells (ILC3s) in response to the gut microbiota ensures maintenance of intestinal barrier function. Here, we examined the mechanisms whereby the immune system detects microbiota in the steady state. A Syk-kinase-coupled signaling pathway in dendritic cells (DCs) was critical for commensal-dependent production of IL-17 and IL-22 by CD4+ T cells. The Syk-coupled C-type lectin receptor Mincle detected mucosal-resident commensals in the Peyer's patches (PPs), triggered IL-6 and IL-23p19 expression, and thereby regulated function of intestinal Th17- and IL-17-secreting ILCs...
January 21, 2019: Immunity
José M Adrover, Carlos Del Fresno, Georgiana Crainiciuc, Maria Isabel Cuartero, María Casanova-Acebes, Linnea A Weiss, Hector Huerga-Encabo, Carlos Silvestre-Roig, Jan Rossaint, Itziar Cossío, Ana V Lechuga-Vieco, Jaime García-Prieto, Mónica Gómez-Parrizas, Juan A Quintana, Ivan Ballesteros, Sandra Martin-Salamanca, Alejandra Aroca-Crevillen, Shu Zhen Chong, Maximilien Evrard, Karl Balabanian, Jorge López, Kiril Bidzhekov, Françoise Bachelerie, Francisco Abad-Santos, Cecilia Muñoz-Calleja, Alexander Zarbock, Oliver Soehnlein, Christian Weber, Lai Guan Ng, Cristina Lopez-Rodriguez, David Sancho, María A Moro, Borja Ibáñez, Andrés Hidalgo
Neutrophils eliminate pathogens efficiently but can inflict severe damage to the host if they over-activate within blood vessels. It is unclear how immunity solves the dilemma of mounting an efficient anti-microbial defense while preserving vascular health. Here, we identify a neutrophil-intrinsic program that enabled both. The gene Bmal1 regulated expression of the chemokine CXCL2 to induce chemokine receptor CXCR2-dependent diurnal changes in the transcriptional and migratory properties of circulating neutrophils...
January 21, 2019: Immunity
Rebecca S Treger, Scott D Pope, Yong Kong, Maria Tokuyama, Manabu Taura, Akiko Iwasaki
Elevated endogenous retrovirus (ERV) transcription and anti-ERV antibody reactivity are implicated in lupus pathogenesis. Overproduction of non-ecotropic ERV (NEERV) envelope glycoprotein gp70 and resultant nephritis occur in lupus-prone mice, but whether NEERV mis-expression contributes to lupus etiology is unclear. Here we identified suppressor of NEERV (Snerv) 1 and 2, Krüppel-associated box zinc-finger proteins (KRAB-ZFPs) that repressed NEERV by binding the NEERV long terminal repeat to recruit the transcriptional regulator KAP1...
January 17, 2019: Immunity
Adam S Dingens, Dana Arenz, Haidyn Weight, Julie Overbaugh, Jesse D Bloom
Anti-HIV broadly neutralizing antibodies (bnAbs) have revealed vaccine targets on the virus's envelope (Env) protein and are themselves promising immunotherapies. The efficacy of bnAb-based therapies and vaccines depends in part on how readily the virus can escape neutralization. Although structural studies can define contacts between bnAbs and Env, only functional studies can define mutations that confer escape. Here, we mapped how all possible single amino acid mutations in Env affect neutralization of HIV by nine bnAbs targeting five epitopes...
January 16, 2019: Immunity
Xiaoyu Liu, Daniel P Nemeth, Daniel B McKim, Ling Zhu, Damon J DiSabato, Olimpia Berdysz, Gowthami Gorantla, Braedan Oliver, Kristina G Witcher, Yufen Wang, Christina E Negray, Rekha S Vegesna, John F Sheridan, Jonathan P Godbout, Matthew J Robson, Randy D Blakely, Phillip G Popovich, Staci D Bilbo, Ning Quan
Interleukin-1 (IL-1) signaling is important for multiple potentially pathogenic processes in the central nervous system (CNS), but the cell-type-specific roles of IL-1 signaling are unclear. We used a genetic knockin reporter system in mice to track and reciprocally delete or express IL-1 receptor 1 (IL-1R1) in specific cell types, including endothelial cells, ventricular cells, peripheral myeloid cells, microglia, astrocytes, and neurons. We found that endothelial IL-1R1 was necessary and sufficient for mediating sickness behavior and drove leukocyte recruitment to the CNS and impaired neurogenesis, whereas ventricular IL-1R1 was critical for monocyte recruitment to the CNS...
January 16, 2019: Immunity
Frédéric Van Gool, Michelle L T Nguyen, Maxwell R Mumbach, Ansuman T Satpathy, Wendy L Rosenthal, Simone Giacometti, Duy T Le, Weihong Liu, Todd M Brusko, Mark S Anderson, Alexander Y Rudensky, Alexander Marson, Howard Y Chang, Jeffrey A Bluestone
Regulatory T (Treg) cells maintain immune tolerance through the master transcription factor forkhead box P3 (FOXP3), which is crucial for Treg cell function and homeostasis. We identified an IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked) syndrome patient with a FOXP3 mutation in the domain swap interface of the protein. Recapitulation of this Foxp3 variant in mice led to the development of an autoimmune syndrome consistent with an unrestrained T helper type 2 (Th2) immune response. Genomic analysis of Treg cells by RNA-sequencing, Foxp3 chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-sequencing), and H3K27ac-HiChIP revealed a specific de-repression of the Th2 transcriptional program leading to the generation of Th2-like Treg cells that were unable to suppress extrinsic Th2 cells...
January 9, 2019: Immunity
Thomas Ciucci, Melanie S Vacchio, Yayi Gao, Francesco Tomassoni Ardori, Julian Candia, Monika Mehta, Yongmei Zhao, Bao Tran, Marion Pepper, Lino Tessarollo, Dorian B McGavern, Rémy Bosselut
Memory CD4+ T cells mediate long-term immunity, and their generation is a key objective of vaccination strategies. However, the transcriptional circuitry controlling the emergence of memory cells from early CD4+ antigen-responders remains poorly understood. Here, using single-cell RNA-seq to study the transcriptome of virus-specific CD4+ T cells, we identified a gene signature that distinguishes potential memory precursors from effector cells. We found that both that signature and the emergence of memory CD4+ T cells required the transcription factor Thpok...
January 8, 2019: Immunity
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