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Abdul Malik Tyagi, Mingcan Yu, Trevor M Darby, Chiara Vaccaro, Jau-Yi Li, Joshua A Owens, Emory Hsu, Jonathan Adams, M Neale Weitzmann, Rheinallt M Jones, Roberto Pacifici
Nutritional supplementation with probiotics can prevent pathologic bone loss. Here we examined the impact of supplementation with Lactobacillus rhamnosus GG (LGG) on bone homeostasis in eugonadic young mice. Micro-computed tomography revealed that LGG increased trabecular bone volume in mice, which was due to increased bone formation. Butyrate produced in the gut following LGG ingestion, or butyrate fed directly to germ-free mice, induced the expansion of intestinal and bone marrow (BM) regulatory T (Treg) cells...
November 9, 2018: Immunity
Tamara Girbl, Tchern Lenn, Lorena Perez, Loïc Rolas, Anna Barkaway, Aude Thiriot, Carlos Del Fresno, Eleanor Lynam, Elin Hub, Marcus Thelen, Gerard Graham, Ronen Alon, David Sancho, Ulrich H von Andrian, Mathieu-Benoit Voisin, Antal Rot, Sussan Nourshargh
Neutrophils require directional cues to navigate through the complex structure of venular walls and into inflamed tissues. Here we applied confocal intravital microscopy to analyze neutrophil emigration in cytokine-stimulated mouse cremaster muscles. We identified differential and non-redundant roles for the chemokines CXCL1 and CXCL2, governed by their distinct cellular sources. CXCL1 was produced mainly by TNF-stimulated endothelial cells (ECs) and pericytes and supported luminal and sub-EC neutrophil crawling...
November 6, 2018: Immunity
Nicholas A Spidale, Katelyn Sylvia, Kavitha Narayan, Bing Miu, Michela Frascoli, Heather J Melichar, Wu Zhihao, Jan Kisielow, Amy Palin, Thomas Serwold, Paul Love, Michihiro Kobayashi, Momoko Yoshimoto, Nitya Jain, Joonsoo Kang
Lineage-committed αβ and γδ T cells are thought to originate from common intrathymic multipotent progenitors following instructive T cell receptor (TCR) signals. A subset of lymph node and mucosal Vγ2+ γδ T cells is programmed intrathymically to produce IL-17 (Tγδ17 cells), however the role of the γδTCR in development of these cells remains controversial. Here we generated reporter mice for the Tγδ17 lineage-defining transcription factor SOX13 and identified fetal-origin, intrathymic Sox13+ progenitors...
November 6, 2018: Immunity
Hao Shi, Chaohong Liu, Haiyan Tan, Yuxin Li, Thanh-Long M Nguyen, Yogesh Dhungana, Cliff Guy, Peter Vogel, Geoffrey Neale, Sherri Rankin, Yongqiang Feng, Junmin Peng, Wufan Tao, Hongbo Chi
Interleukin-2 (IL-2) and downstream transcription factor STAT5 are important for maintaining regulatory T (Treg) cell homeostasis and function. Treg cells can respond to low IL-2 levels, but the mechanisms of STAT5 activation during partial IL-2 deficiency remain uncertain. We identified the serine-threonine kinase Mst1 as a signal-dependent amplifier of IL-2-STAT5 activity in Treg cells. High Mst1 and Mst2 (Mst1-Mst2) activity in Treg cells was crucial to prevent tumor resistance and autoimmunity. Mechanistically, Mst1-Mst2 sensed IL-2 signals to promote the STAT5 activation necessary for Treg cell homeostasis and lineage stability and to maintain the highly suppressive phosphorylated-STAT5+ Treg cell subpopulation...
November 6, 2018: Immunity
Igor Iatsenko, Jean-Philippe Boquete, Bruno Lemaitre
Commensal microbes colonize the gut epithelia of virtually all animals and provide several benefits to their hosts. Changes in commensal populations can lead to dysbiosis, which is associated with numerous pathologies and decreased lifespan. Peptidoglycan recognition proteins (PGRPs) are important regulators of the commensal microbiota and intestinal homeostasis. Here, we found that a null mutation in Drosophila PGRP-SD was associated with overgrowth of Lactobacillus plantarum in the fly gut and a shortened lifespan...
November 3, 2018: Immunity
Shiyang Li, John W Bostick, Jian Ye, Ju Qiu, Bin Zhang, Joseph F Urban, Dorina Avram, Liang Zhou
Innate lymphoid cells (ILCs) are important for mucosal immunity. The intestine harbors all ILC subsets, but how these cells are balanced to achieve immune homeostasis and mount appropriate responses during infection remains elusive. Here, we show that aryl hydrocarbon receptor (Ahr) expression in the gut regulates ILC balance. Among ILCs, Ahr is most highly expressed by gut ILC2s and controls chromatin accessibility at the Ahr locus via positive feedback. Ahr signaling suppresses Gfi1 transcription-factor-mediated expression of the interleukin-33 (IL-33) receptor ST2 in ILC2s and expression of ILC2 effector molecules IL-5, IL-13, and amphiregulin in a cell-intrinsic manner...
November 2, 2018: Immunity
Bing Wu, Song Zhang, Zengli Guo, Gang Wang, Ge Zhang, Ling Xie, Jitong Lou, Xian Chen, Di Wu, Wolfgang Bergmeier, Junnian Zheng, Yisong Y Wan
Pathogenic Th17 (pTh17) cells drive inflammation and immune-pathology, but whether pTh17 cells are a Th17 cell subset whose generation is under specific molecular control remains unaddressed. We found that Ras p21 protein activator 3 (RASA3) was highly expressed by pTh17 cells relative to non-pTh17 cells and was required specifically for pTh17 generation in vitro and in vivo. Mice conditionally deficient for Rasa3 in T cells showed less pathology during experimental autoimmune encephalomyelitis. Rasa3-deficient T cells acquired a Th2 cell-biased program that dominantly trans-suppressed pTh17 cell generation via interleukin 4 production...
November 1, 2018: Immunity
Adeline Crinier, Pierre Milpied, Bertrand Escalière, Christelle Piperoglou, Justine Galluso, Anaïs Balsamo, Lionel Spinelli, Inaki Cervera-Marzal, Mikaël Ebbo, Mathilde Girard-Madoux, Sébastien Jaeger, Emilie Bollon, Sami Hamed, Jean Hardwigsen, Sophie Ugolini, Frédéric Vély, Emilie Narni-Mancinelli, Eric Vivier
Natural killer (NK) cells are innate lymphoid cells (ILCs) involved in antimicrobial and antitumoral responses. Several NK cell subsets have been reported in humans and mice, but their heterogeneity across organs and species remains poorly characterized. We assessed the diversity of human and mouse NK cells by single-cell RNA sequencing on thousands of individual cells isolated from spleen and blood. Unbiased transcriptional clustering revealed two distinct signatures differentiating between splenic and blood NK cells...
November 1, 2018: Immunity
Sarah L Buchan, Lang Dou, Marcus Remer, Steven G Booth, Stuart N Dunn, Chester Lai, Monika Semmrich, Ingrid Teige, Linda Mårtensson, Christine A Penfold, H T Claude Chan, Jane E Willoughby, C Ian Mockridge, Lekh N Dahal, Kirstie L S Cleary, Sonya James, Anne Rogel, Päivi Kannisto, Mats Jernetz, Emily L Williams, Eugene Healy, J Sjef Verbeek, Peter W M Johnson, Björn Frendéus, Mark S Cragg, Martin J Glennie, Juliet C Gray, Aymen Al-Shamkhani, Stephen A Beers
The costimulatory receptor 4-1BB is expressed on activated immune cells, including activated T cells. Antibodies targeting 4-1BB enhance the proliferation and survival of antigen-stimulated T cells in vitro and promote CD8 T cell-dependent anti-tumor immunity in pre-clinical cancer models. We found that T regulatory (Treg) cells infiltrating human or murine tumors expressed high amounts of 4-1BB. Intra-tumoral Treg cells were preferentially depleted by anti-4-1BB mAbs in vivo. Anti-4-1BB mAbs also promoted effector T cell agonism to promote tumor rejection...
October 31, 2018: Immunity
Mounia S Braza, Mandy M T van Leent, Marnix Lameijer, Brenda L Sanchez-Gaytan, Rob J W Arts, Carlos Pérez-Medina, Patricia Conde, Mercedes R Garcia, Maria Gonzalez-Perez, Manisha Brahmachary, Francois Fay, Ewelina Kluza, Susanne Kossatz, Regine J Dress, Fadi Salem, Alexander Rialdi, Thomas Reiner, Peter Boros, Gustav J Strijkers, Claudia C Calcagno, Florent Ginhoux, Ivan Marazzi, Esther Lutgens, Gerry A F Nicolaes, Christian Weber, Filip K Swirski, Matthias Nahrendorf, Edward A Fisher, Raphaël Duivenvoorden, Zahi A Fayad, Mihai G Netea, Willem J M Mulder, Jordi Ochando
Inducing graft acceptance without chronic immunosuppression remains an elusive goal in organ transplantation. Using an experimental transplantation mouse model, we demonstrate that local macrophage activation through dectin-1 and toll-like receptor 4 (TLR4) drives trained immunity-associated cytokine production during allograft rejection. We conducted nanoimmunotherapeutic studies and found that a short-term mTOR-specific high-density lipoprotein (HDL) nanobiologic treatment (mTORi-HDL) averted macrophage aerobic glycolysis and the epigenetic modifications underlying inflammatory cytokine production...
October 30, 2018: Immunity
Aliia R Fatkhullina, Iuliia O Peshkova, Amiran Dzutsev, Turan Aghayev, John A McCulloch, Vishal Thovarai, Jonathan H Badger, Ravi Vats, Prithu Sundd, Hsin-Yao Tang, Andrew V Kossenkov, Stanley L Hazen, Giorgio Trinchieri, Sergei I Grivennikov, Ekaterina K Koltsova
Although commensal flora is involved in the regulation of immunity, the interplay between cytokine signaling and microbiota in atherosclerosis remains unknown. We found that interleukin (IL)-23 and its downstream target IL-22 restricted atherosclerosis by repressing pro-atherogenic microbiota. Inactivation of IL-23-IL-22 signaling led to deterioration of the intestinal barrier, dysbiosis, and expansion of pathogenic bacteria with distinct biosynthetic and metabolic properties, causing systemic increase in pro-atherogenic metabolites such as lipopolysaccharide (LPS) and trimethylamine N-oxide (TMAO)...
October 25, 2018: Immunity
Kristine N Brazin, Robert J Mallis, Andras Boeszoermenyi, Yinnian Feng, Akihiro Yoshizawa, Pedro A Reche, Pavanjeet Kaur, Kevin Bi, Rebecca E Hussey, Jonathan S Duke-Cohan, Likai Song, Gerhard Wagner, Haribabu Arthanari, Matthew J Lang, Ellis L Reinherz
Initial molecular details of cellular activation following αβT cell antigen receptor (TCR) ligation by peptide-major histocompatibility complexes (pMHC) remain unexplored. We determined the nuclear magnetic resonance (NMR) structure of the TCRα subunit transmembrane (TM) domain revealing a bipartite helix whose segmentation fosters dynamic movement. Positively charged TM residues Arg251 and Lys256 project from opposite faces of the helix, with Lys256 controlling immersion depth. Their modification caused stepwise reduction in TCR associations with CD3ζζ homodimers and CD3εγ plus CD3εδ heterodimers, respectively, leading to an activated transcriptome...
October 22, 2018: Immunity
Chuansheng Guo, Zhexu Chi, Danlu Jiang, Ting Xu, Weiwei Yu, Zhen Wang, Sheng Chen, Li Zhang, Qianyun Liu, Xingchen Guo, Xue Zhang, Wenxin Li, Linrong Lu, Yingliang Wu, Bao-Liang Song, Di Wang
Cholesterol metabolism has been linked to immune functions, but the mechanisms by which cholesterol biosynthetic signaling orchestrates inflammasome activation remain unclear. Here, we have shown that NLRP3 inflammasome activation is integrated with the maturation of cholesterol master transcription factor SREBP2. Importantly, SCAP-SREBP2 complex endoplasmic reticulum-to-Golgi translocation was required for optimal activation of the NLRP3 inflammasome both in vitro and in vivo. Enforced cholesterol biosynthetic signaling by sterol depletion or statins promoted NLPR3 inflammasome activation...
October 18, 2018: Immunity
Kenichi Shimada, Rebecca A Porritt, Janet L Markman, Jacqueline Gire O'Rourke, Daiko Wakita, Magali Noval Rivas, Chihiro Ogawa, Lina Kozhaya, Gislâine A Martins, Derya Unutmaz, Robert H Baloh, Timothy R Crother, Shuang Chen, Moshe Arditi
Receptor interacting protein 2 (RIP2) plays a role in sensing intracellular pathogens, but its function in T cells is unclear. We show that RIP2 deficiency in CD4+ T cells resulted in chronic and severe interleukin-17A-mediated inflammation during Chlamydia pneumoniae lung infection, increased T helper 17 (Th17) cell formation in lungs of infected mice, accelerated atherosclerosis, and more severe experimental autoimmune encephalomyelitis. While RIP2 deficiency resulted in reduced conventional Th17 cell differentiation, it led to significantly enhanced differentiation of pathogenic (p)Th17 cells, which was dependent on RORα transcription factor and interleukin-1 but independent of nucleotide oligomerization domain (NOD) 1 and 2...
October 16, 2018: Immunity
Huan Lian, Ru Zang, Jin Wei, Wen Ye, Ming-Ming Hu, Yun-Da Chen, Xia-Nan Zhang, Yi Guo, Cao-Qi Lei, Qing Yang, Wei-Wei Luo, Shu Li, Hong-Bing Shu
Recognition of viral RNA by the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) initiates innate antiviral immune response. How the binding of viral RNA to and activation of the RLRs are regulated remains enigmatic. In this study, we identified ZCCHC3 as a positive regulator of the RLRs including RIG-I and MDA5. ZCCHC3 deficiency markedly inhibited RNA virus-triggered induction of downstream antiviral genes, and ZCCHC3-deficient mice were more susceptible to RNA virus infection. ZCCHC3 was associated with RIG-I and MDA5 and functions in two distinct processes for regulation of RIG-I and MDA5 activities...
August 27, 2018: Immunity
Hiroyuki Hosokawa, Jonas Ungerbäck, Xun Wang, Masaki Matsumoto, Keiichi I Nakayama, Sarah M Cohen, Tomoaki Tanaka, Ellen V Rothenberg
No abstract text is available yet for this article.
October 16, 2018: Immunity
Yang Qiu, Yanpeng Xu, Yao Zhang, Hui Zhou, Yong-Qiang Deng, Xiao-Feng Li, Meng Miao, Qiang Zhang, Bo Zhong, Yuanyang Hu, Fu-Chun Zhang, Ligang Wu, Cheng-Feng Qin, Xi Zhou
No abstract text is available yet for this article.
October 16, 2018: Immunity
Gurkan Mollaoglu, Alex Jones, Sarah J Wait, Anandaroop Mukhopadhyay, Sangmin Jeong, Rahul Arya, Soledad A Camolotto, Timothy L Mosbruger, Chris J Stubben, Christopher J Conley, Arjun Bhutkar, Jeffery M Vahrenkamp, Kristofer C Berrett, Melissa H Cessna, Thomas E Lane, Benjamin L Witt, Mohamed E Salama, Jason Gertz, Kevin B Jones, Eric L Snyder, Trudy G Oliver
The major types of non-small-cell lung cancer (NSCLC)-squamous cell carcinoma and adenocarcinoma-have distinct immune microenvironments. We developed a genetic model of squamous NSCLC on the basis of overexpression of the transcription factor Sox2, which specifies lung basal cell fate, and loss of the tumor suppressor Lkb1 (SL mice). SL tumors recapitulated gene-expression and immune-infiltrate features of human squamous NSCLC; such features included enrichment of tumor-associated neutrophils (TANs) and decreased expression of NKX2-1, a transcriptional regulator that specifies alveolar cell fate...
October 16, 2018: Immunity
Assaf Marcus, Amy J Mao, Monisha Lensink-Vasan, LeeAnn Wang, Russell E Vance, David H Raulet
Detection of cytosolic DNA by the enzyme cGAS triggers the production of cGAMP, a second messenger that binds and activates the adaptor protein STING, which leads to interferon (IFN) production. Here, we found that in vivo natural killer (NK) cell killing of tumor cells, but not of normal cells, depends on STING expression in non-tumor cells. Experiments using transplantable tumor models in STING- and cGAS-deficient mice revealed that cGAS expression by tumor cells was critical for tumor rejection by NK cells...
October 16, 2018: Immunity
Zhiqing Li, Shuxun Liu, Junfang Xu, Xiang Zhang, Dan Han, Juan Liu, Meng Xia, Lin Yi, Qicong Shen, Sheng Xu, Linrong Lu, Xuetao Cao
Tissue-resident mast cells are associated with many inflammatory and physiological processes. Although mast cells arise from the yolk sac, the exact ontogeny of adult mast cells remains unclear. Here we have investigated the hematopoietic origin of mast cells using fate-mapping systems. We have shown that early erythro-myeloid progenitors (EMPs), late EMPs, and definitive hematopoietic stem cells (HSCs) each gave rise to mast cells in succession via an intermediate integrin β7+ progenitor. From late embryogenesis to adult, early EMP-derived mast cells were largely replaced by late EMP-derived cells in most connective tissues except adipose and pleural cavity...
October 16, 2018: Immunity
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