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Immunity

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https://www.readbyqxmd.com/read/28423342/a-broadly-neutralizing-antibody-targets-the-dynamic-hiv-envelope-trimer-apex-via-a-long-rigidified-and-anionic-%C3%AE-hairpin-structure
#1
Jeong Hyun Lee, Raiees Andrabi, Ching-Yao Su, Anila Yasmeen, Jean-Philippe Julien, Leopold Kong, Nicholas C Wu, Ryan McBride, Devin Sok, Matthias Pauthner, Christopher A Cottrell, Travis Nieusma, Claudia Blattner, James C Paulson, Per Johan Klasse, Ian A Wilson, Dennis R Burton, Andrew B Ward
Broadly neutralizing antibodies (bnAbs) to HIV delineate vaccine targets and are prophylactic and therapeutic agents. Some of the most potent bnAbs target a quaternary epitope at the apex of the surface HIV envelope (Env) trimer. Using cryo-electron microscopy, we solved the atomic structure of an apex bnAb, PGT145, in complex with Env. We showed that the long anionic HCDR3 of PGT145 penetrated between glycans at the trimer 3-fold axis, to contact peptide residues from all three Env protomers, and thus explains its highly trimer-specific nature...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28423341/glutathione-primes-t-cell-metabolism-for-inflammation
#2
Tak W Mak, Melanie Grusdat, Gordon S Duncan, Catherine Dostert, Yannic Nonnenmacher, Maureen Cox, Carole Binsfeld, Zhenyue Hao, Anne Brüstle, Momoe Itsumi, Christian Jäger, Ying Chen, Olaf Pinkenburg, Bärbel Camara, Markus Ollert, Carsten Bindslev-Jensen, Vasilis Vasiliou, Chiara Gorrini, Philipp A Lang, Michael Lohoff, Isaac S Harris, Karsten Hiller, Dirk Brenner
Activated T cells produce reactive oxygen species (ROS), which trigger the antioxidative glutathione (GSH) response necessary to buffer rising ROS and prevent cellular damage. We report that GSH is essential for T cell effector functions through its regulation of metabolic activity. Conditional gene targeting of the catalytic subunit of glutamate cysteine ligase (Gclc) blocked GSH production specifically in murine T cells. Gclc-deficient T cells initially underwent normal activation but could not meet their increased energy and biosynthetic requirements...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28423340/transforming-growth-factor-%C3%AE-signaling-in-regulatory-t-cells-controls-t-helper-17-cells-and-tissue-specific-immune-responses
#3
Joanne E Konkel, Dunfang Zhang, Peter Zanvit, Cheryl Chia, Tamsin Zangarle-Murray, Wenwen Jin, Songlin Wang, WanJun Chen
Regulatory T cells (Treg cells) perform suppressive functions in disparate tissue environments and against many inflammatory insults, yet the tissue-enriched factor(s) that influence Treg cell phenotype and function remain largely unknown. We have shown a vital role for transforming growth factor-β (TGF-β) signals in safe-guarding specific Treg cell functions. TGF-β signals were dispensable for steady-state Treg cell homeostasis and for Treg cell suppression of T cell proliferation and T helper-1 (Th1) cell differentiation...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28423339/germ-cell-specific-inflammasome-component-nlrp14-negatively-regulates-cytosolic-nucleic-acid-sensing-to-promote-fertilization
#4
Takayuki Abe, Albert Lee, Ramaswami Sitharam, Jordan Kesner, Raul Rabadan, Sagi D Shapira
Cytosolic sensing of nucleic acids initiates tightly regulated programs to limit infection. Oocyte fertilization represents a scenario wherein inappropriate responses to exogenous yet non-pathogen-derived nucleic acids would have negative consequences. We hypothesized that germ cells express negative regulators of nucleic acid sensing (NAS) in steady state and applied an integrated data-mining and functional genomics approach to identify a rheostat of DNA and RNA sensing-the inflammasome component NLRP14. We demonstrated that NLRP14 interacted physically with the nucleic acid sensing pathway and targeted TBK1 (TANK binding kinase 1) for ubiquitination and degradation...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28423338/an-amphibian-host-defense-peptide-is-virucidal-for-human-h1-hemagglutinin-bearing-influenza-viruses
#5
David J Holthausen, Song Hee Lee, Vineeth Tv Kumar, Nicole M Bouvier, Florian Krammer, Ali H Ellebedy, Jens Wrammert, Anice C Lowen, Sanil George, Madhavan Radhakrishna Pillai, Joshy Jacob
Although vaccines confer protection against influenza A viruses, antiviral treatment becomes the first line of defense during pandemics because there is insufficient time to produce vaccines. Current antiviral drugs are susceptible to drug resistance, and developing new antivirals is essential. We studied host defense peptides from the skin of the South Indian frog and demonstrated that one of these, which we named "urumin," is virucidal for H1 hemagglutinin-bearing human influenza A viruses. This peptide specifically targeted the conserved stalk region of H1 hemagglutinin and was effective against drug-resistant H1 influenza viruses...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28423337/homeostatic-immunity-and-the-microbiota
#6
REVIEW
Yasmine Belkaid, Oliver J Harrison
The microbiota plays a fundamental role in the induction, education, and function of the host immune system. In return, the host immune system has evolved multiple means by which to maintain its symbiotic relationship with the microbiota. The maintenance of this dialogue allows the induction of protective responses to pathogens and the utilization of regulatory pathways involved in the sustained tolerance to innocuous antigens. The ability of microbes to set the immunological tone of tissues, both locally and systemically, requires tonic sensing of microbes and complex feedback loops between innate and adaptive components of the immune system...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28423336/lung-homeostasis-influence-of-age-microbes-and-the-immune-system
#7
REVIEW
Clare M Lloyd, Benjamin J Marsland
Pulmonary immune homeostasis is maintained by a network of tissue-resident cells that continually monitor the external environment, and in health, instruct tolerance to innocuous inhaled particles while ensuring that efficient and rapid immune responses can be mounted against invading pathogens. Here we review the multiple pathways that underlie effective lung immunity in health, and discuss how these may be affected by external environmental factors and contribute to chronic inflammation during disease. In this context, we examine the current understanding of the impact of the microbiota in immune development and function and in the setting of the threshold for immune responses that maintains the balance between tolerance and chronic inflammation in the lung...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28423335/regionalized-development-and-maintenance-of-the-intestinal-adaptive-immune-landscape
#8
REVIEW
William W Agace, Kathy D McCoy
The intestinal immune system has the daunting task of protecting us from pathogenic insults while limiting inflammatory responses against the resident commensal microbiota and providing tolerance to food antigens. This role is particularly impressive when one considers the vast mucosal surface and changing landscape that the intestinal immune system must monitor. In this review, we highlight regional differences in the development and composition of the adaptive immune landscape of the intestine and the impact of local intrinsic and environmental factors that shape this process...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28423334/two-strings-in-one-bow-pd-1-negatively-regulates-via-co-receptor-cd28-on-t-cells
#9
Janna Krueger, Christopher E Rudd
The identity of PD-1 dependency on other receptors and signaling has been unclear. In a recent issue of Science, Hui et al. (2017) and Kamphorst et al. (2017) now show that CD28 expression is a target of PD-1-associated phosphatases and is needed for T cell expansion in anti-PD-1 immunotherapy.
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28423333/hunting-down-the-hiv-1-reservoir-a-starring-role-for-antibodies
#10
Hugo Mouquet
The persistence of viruses "hidden" in a reservoir of latently infected CD4(+) T cells under antiretroviral therapy is the major obstacle to an HIV-1 cure. Recently published in Nature, two seminal studies from Descours et al. (2017) and Nishimura et al. (2017) bring hope for tracking and possibly eradicating the HIV-1 reservoir.
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28423332/caught-in-the-crossfire-gsh-controls-t-cell-metabolic-reprogramming
#11
Ramon I Klein Geltink, David O'Sullivan, Erika L Pearce
T cell activation and proliferation critical for protective immunity depend on appropriate rewiring of cellular metabolism. In this issue of Immunity, Mak et al. (2017) show that the antioxidant gluthathione (GSH) controls reactive oxygen species (ROS)-dependent engagement of metabolic signaling pathways that lead to protective T cell responses.
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28423331/cell-intrinsic-defense-at-the-epithelial-border-wall-salmonella-pays-the-price
#12
Sky W Brubaker, Denise M Monack
Within the gut, Salmonella-infected enterocytes are expelled into the lumen, limiting pathogen replication. In this issue of Immunity, Rauch et al. (2017) expand our understanding of this cell-intrinsic response by characterizing the genetic determinants that control the expulsion and death of epithelial cells.
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28423330/the-birds-the-bees-and-innate-immunity
#13
Glen N Barber
The cytoplasm is usually a DNA-free zone, but during fertilization, sperm DNA enters oocyte cytoplasm and could potentially trigger a response. Abe et al. (2017) identify NLRP14 as a germ-cell-specific negative regulator of DNA sensing that may be of particular importance during fertilization.
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28423329/the-dynamic-cytokine-niche
#14
Frank P Assen, Michael Sixt
Immune cells communicate using cytokine signals, but the quantitative rules of this communication aren't clear. In this issue of Immunity, Oyler-Yaniv et al. (2017) suggest that the distribution of a cytokine within a lymphatic organ is primarily governed by the local density of cells consuming it.
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28423328/treating-flu-with-skin-of-frog
#15
James E Crowe
Glands in frog skin secrete substances that possess broad antimicrobial function. Holthausen et al. mined this soup of natural products and discovered a peptide that destroys diverse human influenza strains (Holthausen et al., 2017). This study points the way to the discovery of novel anti-influenza molecules targeting conserved elements on influenza surface proteins.
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28410991/naip-nlrc4-inflammasomes-coordinate-intestinal-epithelial-cell-expulsion-with-eicosanoid-and-il-18-release-via-activation-of-caspase-1-and-8
#16
Isabella Rauch, Katherine A Deets, Daisy X Ji, Jakob von Moltke, Jeannette L Tenthorey, Angus Y Lee, Naomi H Philip, Janelle S Ayres, Igor E Brodsky, Karsten Gronert, Russell E Vance
Intestinal epithelial cells (IECs) form a critical barrier against pathogen invasion. By generation of mice in which inflammasome expression is restricted to IECs, we describe a coordinated epithelium-intrinsic inflammasome response in vivo. This response was sufficient to protect against Salmonella tissue invasion and involved a previously reported IEC expulsion that was coordinated with lipid mediator and cytokine production and lytic IEC death. Excessive inflammasome activation in IECs was sufficient to result in diarrhea and pathology...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28410990/tyrosine-kinase-syk-licenses-myd88-adaptor-protein-to-instigate-il-1%C3%AE-mediated-inflammatory-disease
#17
Prajwal Gurung, Gaofeng Fan, John R Lukens, Peter Vogel, Nicholas K Tonks, Thirumala-Devi Kanneganti
Mice carrying a hypomorphic point mutation in the Ptpn6 gene (Ptpn6(spin) mice) develop an inflammatory skin disease that resembles neutrophilic dermatosis in humans. Here, we demonstrated that interleukin-1α (IL-1α) signaling through IL-1R and MyD88 in both stromal and immune cells drive inflammation in Ptpn6(spin) mice. We further identified SYK as a critical kinase that phosphorylates MyD88, promoted MyD88-dependent signaling and mediates dermatosis in Ptpn6(spin) mice. Our studies further demonstrated that SHP1 encoded by Ptpn6 binds and suppresses SYK activation to inhibit MyD88 phosphorylation...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28410989/polycomb-repressive-complex-2-mediated-chromatin-repression-guides-effector-cd8-t-cell-terminal-differentiation-and-loss-of-multipotency
#18
Simon M Gray, Robert A Amezquita, Tianxia Guan, Steven H Kleinstein, Susan M Kaech
Understanding immunological memory formation depends on elucidating how multipotent memory precursor (MP) cells maintain developmental plasticity and longevity to provide long-term immunity while other effector cells develop into terminally differentiated effector (TE) cells with limited survival. Profiling active (H3K27ac) and repressed (H3K27me3) chromatin in naive, MP, and TE CD8(+) T cells during viral infection revealed increased H3K27me3 deposition at numerous pro-memory and pro-survival genes in TE relative to MP cells, indicative of fate restriction, but permissive chromatin at both pro-memory and pro-effector genes in MP cells, indicative of multipotency...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28410988/fc-optimized-anti-cd25-depletes-tumor-infiltrating-regulatory-t-cells-and-synergizes-with-pd-1-blockade-to-eradicate-established-tumors
#19
Frederick Arce Vargas, Andrew J S Furness, Isabelle Solomon, Kroopa Joshi, Leila Mekkaoui, Marta H Lesko, Enrique Miranda Rota, Rony Dahan, Andrew Georgiou, Anna Sledzinska, Assma Ben Aissa, Dafne Franz, Mariana Werner Sunderland, Yien Ning Sophia Wong, Jake Y Henry, Tim O'Brien, David Nicol, Ben Challacombe, Stephen A Beers, Samra Turajlic, Martin Gore, James Larkin, Charles Swanton, Kerry A Chester, Martin Pule, Jeffrey V Ravetch, Teresa Marafioti, Karl S Peggs, Sergio A Quezada
CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28389069/a-tunable-diffusion-consumption-mechanism-of-cytokine-propagation-enables-plasticity-in-cell-to-cell-communication-in-the-immune-system
#20
Alon Oyler-Yaniv, Jennifer Oyler-Yaniv, Benjamin M Whitlock, Zhiduo Liu, Ronald N Germain, Morgan Huse, Grégoire Altan-Bonnet, Oleg Krichevsky
Immune cells communicate by exchanging cytokines to achieve a context-appropriate response, but the distances over which such communication happens are not known. Here, we used theoretical considerations and experimental models of immune responses in vitro and in vivo to quantify the spatial extent of cytokine communications in dense tissues. We established that competition between cytokine diffusion and consumption generated spatial niches of high cytokine concentrations with sharp boundaries. The size of these self-assembled niches scaled with the density of cytokine-consuming cells, a parameter that gets tuned during immune responses...
April 18, 2017: Immunity
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