Type 1 innate lymphocytes comprise two developmentally divergent lineages, type 1 helper innate lymphoid cells (hILC1s) and conventional NK cells (cNKs).
Immunology
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Teaching and Learning Immunology. Information you never would have searched for!
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Gilbert C FAURE
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This protocol uses a microfluidic flow-focusing device to encapsulate single cells, enabling high-throughput sequencing of the paired immune receptor repertoire from millions of lymphocytes at the single-cell level. 
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 Antimicrobial peptidesAntimicrobial peptides (AMPs), also called host defense peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides. These peptides are potent, broad spectrum antibiotics which demonstrate potential as novel therapeutic agents. Antimicrobial peptides (AMPs), also called host defense peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental ...
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Kyle Burrows from talks about a hot topic in immunology, innate lymphoid cells, in his #ImmunologyProfiles video https://t.co/00bD9M50so
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RT @argoicoechea: The Regulation of Immunological Processes by Peripheral Neurons in Homeostasis and Disease
Gilbert C FAURE's insight:
The nervous system and the immune system are the principal sensory interfaces between the internal and external environment. They are responsible for recognizing, integrating, and responding to varied stimuli, and have the capacity to form memories of these encounters leading to learned or ‘adaptive’ future responses. We review current understanding of the cross-regulation between these systems. The autonomic and somatosensory nervous systems regulate both the development and deployment of immune cells, with broad functions that impact on hematopoiesis as well as on priming, migration, and cytokine production. In turn, specific immune cell subsets contribute to homeostatic neural circuits such as those controlling metabolism, hypertension, and the inflammatory reflex. We examine the contribution of the somatosensory system to autoimmune, autoinflammatory, allergic, and infectious processes in barrier tissues and, in this context, discuss opportunities for therapeutic manipulation of neuro-immune interactions.
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RT @Cancer_Cell: Munn @MCG_AUG & Mellor @StudentsNCL review IDO in the tumor microenvironment https://t.co/X4LZZSgicQ in Trends Immunol.
Gilbert C FAURE's insight:
Indoleamine 2,3-dioxygenase (IDO) has immunoregulatory roles associated with tryptophan metabolism. These include counter-regulation (controlling inflammation) and acquired tolerance in T cells. Recent findings reveal that IDO can be triggered by innate responses during tumorigenesis, and also by attempted T cell activation, either spontaneous or due to immunotherapy. Here we review the current understanding of mechanisms by which IDO participates in the control of inflammation and in peripheral tolerance. Focusing on the tumor microenvironment, we examine the role of IDO in response to apoptotic cells and the impact of IDO on Treg cell function. We discuss how the counter-regulatory and tolerogenic functions of IDO can be targeted for cancer immunotherapy and present an overview of the current clinical progress in this area. Trends
IDO can be induced in the tumor microenvironment by the spontaneous inflammation and T cell activation associated with many tumors; however, IDO may also be induced reactively, in response to inflammation induced by antitumor immunotherapy. IDO is rapidly induced when mice are challenged with apoptotic cells. Inhibiting or genetically deleting IDO results in loss of self-tolerance to apoptotic cell-associated antigens, and susceptibility to lupus-like autoimmunity. DNA-containing nanoparticles can induce immunosuppressive IDO via a pathway dependent on the STING sensor of cytosolic DNA. When Treg cells are activated in the presence of IDO, they upregulate a highly suppressive phenotype driven by the PTEN lipid phosphatase. In vivo, challenge with apoptotic cells triggers IDO-mediated induction of PTEN-expressing Treg cells. In tumors, IDO induction by apoptotic cells may become relevant as the tumor attempts to inhibit immune responses to dying tumor cells following chemotherapy or immunotherapy.
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Staphylococcal enterotoxin B (SEB) of Staphylococcus aureus, and related superantigenic toxins produced by myriad microbes, are potent stimulators of the immune system causing a variety of human diseases from transient food poisoning to lethal...
Gilbert C FAURE's insight:
SEB
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Mol Ecol. 2016 Feb 2. doi: 10.1111/mec.13558. [Epub ahead of print]
Gilbert C FAURE's insight:
Abstract
The complement system is an innate immunity effector mechanism its action is antagonized by a wide array of pathogens and complement evasion determines the virulence of several infections. We investigated the evolutionary history of the complement system and of bacterial-encoded complement-interacting proteins. Complement components targeted by several pathogens evolved under strong selective pressure in primates with selection acting on residues at the contact interface with microbial/viral proteins. Positively selected sites in CFH and C4BPA account for the human specificity of gonococcal infection. Bacterial interactors evolved adaptively as well with selected sites located at interaction surfaces with primate complement proteins. These results epitomize the expectation under a genetic conflict scenario whereby the host's and the pathogen's genes evolve within binding avoidance-binding seeking dynamics. In silico mutagenesis and protein-protein docking analyses supported this by showing that positively selected sites both in the host's and in the pathogen's interacting partner modulate binding. This article is protected by copyright. All rights reserved.
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Super exciting results - Toll Receptor-Mediated Hippo Signaling Controls Innate Immunity in Drosophila: https://t.co/6Vjgs9qDDn
Gilbert C FAURE's insight:
Highlights
•Hippo-Yki signaling is required for antimicrobial response in Drosophila•cact is a direct target of the Yki-Sd transcription factor complex•Gram-positive bacteria acutely activate Hippo-Yki signaling in vivo•The Toll-Myd88-Pelle cascade activates Hpo by phosphorylating and degrading Cka
Summary
The Hippo signaling pathway functions through Yorkie to control tissue growth and homeostasis. How this pathway regulates non-developmental processes remains largely unexplored. Here, we report an essential role for Hippo signaling in innate immunity whereby Yorkie directly regulates the transcription of the Drosophila IκB homolog, Cactus, in Toll receptor-mediated antimicrobial response. Loss of Hippo pathway tumor suppressors or activation of Yorkie in fat bodies, theDrosophila immune organ, leads to elevated cactus mRNA levels, decreased expression of antimicrobial peptides, and vulnerability to infection by Gram-positive bacteria. Furthermore, Gram-positive bacteria acutely activate Hippo-Yorkie signaling in fat bodies via the Toll-Myd88-Pelle cascade through Pelle-mediated phosphorylation and degradation of the Cka subunit of the Hippo-inhibitory STRIPAK PP2A complex. Our studies elucidate a Toll-mediated Hippo signaling pathway in antimicrobial response, highlight the importance of regulating IκB/Cactus transcription in innate immunity, and identify Gram-positive bacteria as extracellular stimuli of Hippo signaling under physiological settings.
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December 2015 saw the conclusion of the STROMA ITN project – a programme involving eminent immunologists, several different companies, early career researchers and experienced researchers.
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An international, open-access journal publishing top-quality, novel methods and technology development, as well as significant improvements to established techniques in basic, translational, and clinical cell and gene therapy.
Gilbert C FAURE's insight:
Transgenic expression of antigen-specific T-cell receptor (TCR) genes is a promising approach for immunotherapy against infectious diseases and cancers. A key to the efficient application of this approach is the rapid and specific isolation and cloning of TCRs. Current methods are often labor-intensive, nonspecific, and/or relatively slow. Here, we describe an efficient system for antigen-specific αβTCR cloning and CDR3 substitution. We demonstrate the capability of cloning influenza-specific TCRs within 10 days using single-cell polymerase chain reaction (PCR) and Gibson Assembly techniques. This process can be accelerated to 5 days by generating receptor libraries, requiring only the exchange of the antigen-specific CDR3 region into an existing backbone. We describe the construction of this library for human γδ TCRs and report the cloning and expression of a TRGV9/TRDV2 receptor that is activated by zoledronic acid. The functional activity of these αβ and γδ TCRs can be characterized in a novel reporter cell line (Nur77-GFP Jurkat 76 TCRα–β–) for screening of TCR specificity and avidity. In summary, we provide a rapid method for the cloning, expression, and functional characterization of human and mouse TCRs that can assist in the development of TCR-mediated therapeutics. OPEN?
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Idiopathic hypogammaglobulinaemia, including common variable immune deficiency (CVID), has a heterogeneous clinical phenotype.
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Author Summary The human complement system is a connected network of blood proteins capable of recognizing and eliminating microbial intruders.
Gilbert C FAURE's insight:
Pathogens that traffic in blood, lymphatics, or interstitial fluids must adopt strategies to evade innate immune defenses, notably the complement system. Through recruitment of host regulators of complement to their surface, many pathogens are able to escape complement-mediated attack. The Lyme disease spirochete, Borrelia burgdorferi, produces a number of surface proteins that bind to factor H related molecules, which function as the dominant negative regulator of the alternative pathway of complement. Relatively less is known about how B. burgdorferi evades the classical pathway of complement despite the observation that some sensu lato strains are sensitive to classical pathway activation. Here we report that the borrelial lipoprotein BBK32 potently and specifically inhibits the classical pathway by binding with high affinity to the initiating C1 complex of complement. In addition, B. burgdorferi cells that produce BBK32 on their surface bind to both C1 and C1r and a serum sensitive derivative of B. burgdorferi is protected from killing via the classical pathway in a BBK32-dependent manner. Subsequent biochemical and biophysical approaches localized the anti-complement activity of BBK32 to its globular C-terminal domain. Mechanistic studies reveal that BBK32 acts by entrapping C1 in its zymogen form by binding and inhibiting the C1 subcomponent, C1r, which serves as the initiating serine protease of the classical pathway. To our knowledge this is the first report of a spirochetal protein acting as a direct inhibitor of the classical pathway and is the only example of a biomolecule capable of specifically and noncovalently inhibiting C1/C1r. By identifying a unique mode of complement evasion this study greatly enhances our understanding of how pathogens subvert and potentially manipulate host innate immune systems.
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The membrane attack complex is a heteromeric assembly of complement proteins where multiple copies of C9 are recruited by the C5b678 complex to form lytic pores in pathogen membranes.
Gilbert C FAURE's insight:
The membrane attack complex (MAC)/perforin-like protein complement component 9 (C9) is the major component of the MAC, a multi-protein complex that forms pores in the membrane of target pathogens. In contrast to homologous proteins such as perforin and the cholesterol-dependent cytolysins (CDCs), all of which require the membrane for oligomerisation, C9 assembles directly onto the nascent MAC from solution. However, the molecular mechanism of MAC assembly remains to be understood. Here we present the 8 Å cryo-EM structure of a soluble form of the poly-C9 component of the MAC. These data reveal a 22-fold symmetrical arrangement of C9 molecules that yield an 88-strand pore-forming β-barrel. The N-terminal thrombospondin-1 (TSP1) domain forms an unexpectedly extensive part of the oligomerisation interface, thus likely facilitating solution-based assembly. These TSP1 interactions may also explain how additional C9 subunits can be recruited to the growing MAC subsequent to membrane insertion.
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The membrane attack complex (MAC) is an immune effector that kills pathogens by forming pores in their membrane.
Gilbert C FAURE's insight:
In response to complement activation, the membrane attack complex (MAC) assembles from fluid-phase proteins to form pores in lipid bilayers. MAC directly lyses pathogens by a ‘multi-hit’ mechanism; however, sublytic MAC pores on host cells activate signalling pathways. Previous studies have described the structures of individual MAC components and subcomplexes; however, the molecular details of its assembly and mechanism of action remain unresolved. Here we report the electron cryo-microscopy structure of human MAC at subnanometre resolution. Structural analyses define the stoichiometry of the complete pore and identify a network of interaction interfaces that determine its assembly mechanism. MAC adopts a ‘split-washer’ configuration, in contrast to the predicted closed ring observed for perforin and cholesterol-dependent cytolysins. Assembly precursors partially penetrate the lipid bilayer, resulting in an irregular β-barrel pore. Our results demonstrate how differences in symmetric and asymmetric components of the MAC underpin a molecular basis for pore formation and suggest a mechanism of action that extends beyond membrane penetration.
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The focus of this eBook is to bring new insights into central immune tolerance. To fulfill that, much has been discussed about the master in the regulation of tolerance, the autoimmune regulator...
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International Congress of Immunology 2016, 21-26 August, Melbourne, Australia
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Companies make the antibodies, but it’s up to you to make sure they work in your experiments.
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During an immune reaction, some antigen-experienced CD4 T cells relocate from secondary lymphoid organs (SLOs) to the bone marrow (BM) in a CD49b-dependent manner and reside and rest there as professional memory CD4 T cells.
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Exercise #Immunology studies the effect of exercise on the immune system https://t.co/cFgXWJBwxG
Gilbert C FAURE's insight:
not recent but referring to old teaching courses
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Tissue-resident regulatory T cells are balancing between tumor immunity and immunopathology
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Highlights •ImmuneSigDB: Collection of ∼5,000 gene sets derived from ∼400 immunological studies•Includes a wide range of mouse and human immune cell states and perturbations•Designed for use with GSEA and an approach called Leading Edge Metagene analysis•ImmuneSigDB identified shared and unique biology in human and mouse sepsis response Via Krishan Maggon
Krishan Maggon 's curator insight,
January 31, 2016 2:54 AM
Immunity
Volume 44, Issue 1, p194–206, 19 January 2016 Jernej Godec, Yan Tan, Arthur Liberzon, Pablo Tamayo, Sanchita Bhattacharya, Atul J. Butte, Jill P. Mesirov , W. Nicholas Haining
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Progress in the use of swine in developmental immunology of B and T lymphocytes
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thks swines
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The generation of phagocytic cups and immunological synapses are crucial events of the innate and adaptive immune responses, respectively. They are triggered by distinct immune receptors and performed by different cell types.
Gilbert C FAURE's insight:
The generation of phagocytic cups and immunological synapses are crucial events of the innate and adaptive immune responses, respectively. They are triggered by distinct immune receptors and performed by different cell types. However, growing experimental evidence shows that a very close series of molecular and cellular events control these two processes. Thus, the tight and dynamic interplay between receptor signaling, actin and microtubule cytoskeleton, and targeted vesicle traffic are all critical features to build functional phagosomes and immunological synapses. Interestingly, both phagocytic cups and immunological synapses display particular spatial and temporal patterns of receptors and signaling molecules, leading to the notion of “phagocytic synapse.” Here, we discuss both types of structures, their organization, and the mechanisms by which they are generated and regulated.
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Type 1 innate lymphocytes comprise two developmentally divergent lineages, type 1 helper innate lymphoid cells (hILC1s) and conventional NK cells (cNKs). All type 1 innate lymphocytes (ILCs) express the transcription factor T-bet, but cNKs additionally express Eomesodermin (Eomes). We show that deletion of Eomes alleles at the onset of type 1 ILC maturation using NKp46-Cre imposes a substantial block in cNK development. Formation of the entire lymphoid and nonlymphoid type 1 ILC compartment appears to require the semiredundant action of both T-bet and Eomes. To determine if Eomes is sufficient to redirect hILC1 development to a cNK fate, we generated transgenic mice that express Eomes when and where T-bet is expressed using Tbx21 locus control to drive expression of Eomes codons. Ectopic Eomes induces cNK-like properties across the lymphoid and nonlymphoid type 1 ILC compartments. Subsequent to their divergent lineage specification, hILC1s and cNKs thus possess substantial developmental plasticity.