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Natural Killer Cell Education and the Response to Infection and Cancer Therapy: Stay Tuned

Natural Killer Cell Education and the Response to Infection and Cancer Therapy: Stay Tuned | Immunology | Scoop.it
The functional capacities of natural killer (NK) cells differ within and between individuals,
reflecting considerable genetic variation. ‘Licensing/arming’, ‘disarming’, and ‘tuning’
are models that have been proposed to explain how interactions between MHC class I
molecules and their cognate inhibitory receptors – Ly49 in mice and KIR in humans
– ‘educate’ NK cells for variable reactivity and sensitivity to inhibition. In this
review we discuss recent progress toward understanding the genetic, epigenetic, and
molecular features that titrate NK effector function and inhibition, and the impact
of variable NK cell education on human health and disease.

Via Krishan Maggon
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Immunology
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Gilbert C FAURE's insight:

This topic is focusing mainly on fundamental systemic immunology.

 

Feel free to browse other related topics!

Mucosal Immunity:

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Immunology and Biotherapies

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Autoimmunity

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Allergy and clinical immunology:

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History of Immunology

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Sodium in the microenvironment regulates immune responses and tissue homeostasis

Sodium in the microenvironment regulates immune responses and tissue homeostasis | Immunology | Scoop.it
Dietary salt can have direct effects on immune cell subsets as well as indirect effects through intestinal dysbiosis. We are beginning to appreciate that high salt diets not only are associated with increased risk of cardiovascular disease but also have marked effects on immune responses.
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Regulatory T cells mediate specific suppression by depleting peptide–MHC class II from dendritic cells

Regulatory T cells mediate specific suppression by depleting peptide–MHC class II from dendritic cells | Immunology | Scoop.it
Regulatory T cells suppress target cells through diverse mechanisms. Shevach and colleagues demonstrate that regulatory T cells in vivo strip complexes of cognate peptide and major histocompatibility complex class II from dendritic cells and thereby help to maintain immune homeostasis.

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Where do memory B cells get reactivated? | Immunopaedia

Where do memory B cells get reactivated? | Immunopaedia | Immunology | Scoop.it
Vaccines harness this arm of immunity by typically inducing long lived plasma cells and/or memory B cells (MBC) that secrete antibodies (Ab)*.Unlike plasma cells, MBCs do not continuously produce Abs and require antigen presentation prior to Ab secretion.
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subcapsular niche

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Cancer Neoantigens | Annual Review of Immunology

Cancer Neoantigens | Annual Review of Immunology | Immunology | Scoop.it
Malignant transformation of cells depends on accumulation of DNA damage. Over the past years we have learned that the T cell–based immune system frequently responds to the neoantigens that arise as a consequence of this DNA damage. Furthermore, recognition of neoantigens appears an important driver of the clinical activity of both T cell checkpoint blockade and adoptive T cell therapy as cancer immunotherapies. Here we review the evidence for the relevance of cancer neoantigens in tumor control and the biological properties of these antigens. We discuss recent technological advances utilized to identify neoantigens, and the T cells that recognize them, in individual patients. Finally, we discuss strategies that can be employed to exploit cancer neoantigens in clinical interventions.

Expected final online publication date for the Annual Review of Immunology Volume 37 is April 26, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Viruses | Free Full-Text | Cytokine Signature Associated with Disease Severity in Dengue

Viruses | Free Full-Text | Cytokine Signature Associated with Disease Severity in Dengue | Immunology | Scoop.it
Dengue is the most rapidly spreading viral disease transmitted by the bite of infected Aedes mosquitos. The pathogenesis of dengue is still unclear; although host immune responses and virus serotypes have been proposed to contribute to disease severity.
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CARD–BCL-10–MALT1 signalling in protective and pathological immunity

CARD–BCL-10–MALT1 signalling in protective and pathological immunity | Immunology | Scoop.it
CARD protein–BCL-10–MALT1 (CBM) signalosomes are key regulators of innate and adaptive immunity and inflammation. This Review summarizes the regulation and function of CBM signalling for host defence and tissue homeostasis and the pathophysiological consequences of genetic CBM alterations in human disease.
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Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells

Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells | Immunology | Scoop.it
Transforming growth factor-β1 (TGF-β1) is one of very few cytokines produced in a latent form, requiring activation to exert any of its vastly diverse effects on development, immunity, and cancer. Regulatory T cells (Tregs) suppress immune cells within close proximity by activating latent TGF-β1 presented by GARP to integrin αVβ8 on their surface. We solved the crystal structure of GARP:latent TGF-β1 bound to an antibody that stabilizes the complex and blocks release of active TGF-β1. This reveals how GARP exploits an unusual medley of interactions, including fold complementation by the N terminus of TGF-β1, to chaperone and orient the cytokine for binding and activation by αVβ8. Thus, this work further elucidates the mechanism of antibody-mediated blockade of TGF-β1 activation and immunosuppression by Tregs.
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Camouflage and interception: how pathogens evade detection by intracellular nucleic acid sensors - Unterholzner - - Immunology - Wiley Online Library

Camouflage and interception: how pathogens evade detection by intracellular nucleic acid sensors - Unterholzner - - Immunology - Wiley Online Library | Immunology | Scoop.it
Immune evasion strategies employed by intracellular pathogens Pathogens and their hosts co‐evolve, and there are clear signs of selective pressure on host factors such as DNA and RNA sensors on the one hand and pathogen‐encoded immune evasion proteins on the other.65-67 Immunomodulatory proteins and virulence factors are finely tuned to adapt to the host range and life cycle of the pathogen. The precise interplay between host and pathogen factors is often unique, and can differ in different host organisms, cell types and among even closely related pathogens. However, mapping these host–pathogen interactions at a molecular level can provide clues about the importance of host signalling cascades, can help us to understand changes in species specificity and virulence of emerging pathogens, and aid in the design of vaccine vectors. As PRR signalling pathways are being characterized in more molecular detail, the intricate counterstrategies employed by pathogens to evade recognition are also becoming apparent. Some general principles by which intracellular pathogens hide from detection or intercept the cell's signalling cascades are described below. Sequestration of PAMPs Pathogens that reside inside host cells are already sheltered from the immune system to some extent, by avoiding exposure to antibodies or complement components. However, due to the existence of intracellular PRRs, additional camouflage strategies are essential for the establishment of infection. Intracellular bacteria and protozoan parasites often co‐opt vacuoles as a niche for replication, which prevents pathogen‐derived nucleic acids and other PAMPs from being exposed to the cell's PRRs. Hence, detection of intracellular nucleic acids during bacterial infection often requires the presence of bacterial secretion systems. For instance, the type VII secretion system ESX from Mycobacterium tuberculosis is responsible for the exposure of bacterial DNA to cGAS in macrophages, but also secretes virulence factors that interfere with host functions.56, 68 Viruses require greater access to host factors for replication than bacteria, but also try to shield their nucleic acids from detection. Some RNA viruses, including Dengue virus and hepatitis C virus, sequester their genome and replication machinery in membrane‐bound compartments, which function to create locally high concentrations of replication factors, as well as hiding viral RNA genomes from recognition by RIG‐I.69, 70 Human immunodeficiency virus type 1 carries out reverse transcription and replication of its genome inside its capsid, which contains selective pores to allow entry for nucleotides from the host cell, while shielding viral DNA from recognition by cGAS.71 Modification of viral RNA and DNA Many pathogens aim to keep PAMP levels at a minimum: coronaviruses for instance quickly degrade any excessive dsRNA formed during the viral life cycle,72 and Group B streptococcus degrades cyclic di‐AMP using an ectonuclease.73 However, the production of nucleic acid PAMPs cannot be avoided altogether; thus, more sophisticated strategies of camouflage have evolved, so that the pathogen can blend into the cellular environment. As viral RNA polymerases generate RNA species with a 5′ triphosphate moiety, many viruses employ additional strategies to modify their RNA, so that it is not recognized efficiently by RIG‐I. For instance, Picornaviridae, Caliciviridae and Astroviridae covalently attach a protein, Vpg, to the 5′ end of viral RNAs, which prevents RIG‐I‐mediated recognition.15 Processing of the negative‐strand ssRNA genome of members of the Bornaviridae and Bunyaviridae families involves the cleavage of the first nucleotide by a viral endonuclease to generate a monophosphate group at the 5′ end.74 Viruses that transcribe their mRNAs in the nucleus, including the DNA viruses of the Herpesviridae and Papillomaviridae families and retroviruses such as human immunodeficiency virus, co‐opt the cell's own capping machinery to protect the 5′ end of their mRNAs with a 7‐methylguanosine cap, while others, including IAV, use ‘cap snatching’ to remove the capped 5′ ends from cellular mRNAs and incorporate them into viral RNA transcripts.75 Many viruses, including poxviruses and flaviviruses, encode their own capping enzymes that synthesize RNA caps that are indistinguishable from the mammalian cap structure.75 Yellow fever virus in addition recapitulates the 2′ O‐methylation of the first RNA nucleotide next to the cap, which is found in cellular mRNAs and further decreases recognition by RIG‐I.76 Bacteria and protozoa also cap their mRNAs, but not always with 100% efficiency. RNA derived from intracellular bacteria can activate the RNA sensing pathway if it reaches the cytosol, but it remains to be determined whether this is important during infection.77 So far, it is not known whether DNA modifications could prevent recognition by cGAS or other DNA sensors. It has been proposed that IFI16 may be able to distinguish viral DNA from the cell's own genome by recognizing longer (>40 nucleotides) stretches of free DNA,43, 44 and the detection of DNA by cGAS has also been shown to be length‐dependent.78 It remains to be tested whether the assembly of nucleosomes on the genomes of DNA viruses such as herpesviruses and papillomaviruses could be a strategy to limit their detection by intracellular DNA sensors. Degradation and inhibition of host signalling factors All intracellular pathogens encode virulence factors that interfere with the host's signalling cascades. Viral immunomodulatory proteins are usually expressed as immediate early genes, or are even part of the viral particle, so that they are able to inhibit the host's signalling cascades as soon as PAMPs are detected early in infection. Intracellular bacteria employ secretion systems to transport effector proteins through the vacuolar and bacterial membranes into the host cell, whereas protozoans can secrete virulence factors via exosomes or other membrane‐bound vesicles. A vast repertoire of virulence factors that influence the cell's innate immune signalling cascades have been described, particularly in viruses, which often dedicate a large portion of their genome to interfering with the host's innate immune response. Although many viruses encode only a few proteins, these are often multi‐functional and target several key host factors. Large DNA viruses, such as poxviruses and herpesviruses, encode a larger repertoire of dozens of immunomodulatory proteins that interfere with anti‐viral signalling cascades in the cell at multiple points.79, 80 Bacteria and protozoa encode thousands of genes, and so have an even greater capacity to interfere with host functions, but comparatively few immune evasion proteins have been described so far, with many pathogen‐encoded effector proteins still uncharacterized.3, 4, 64 Many pathogens have evolved similar strategies to inhibit the innate immune signalling cascades in the host cell: virulence factors act to either eliminate host signalling factors by degradation, sequester them or block their function in the signalling cascade. As we learn more about the regulation of innate immune signalling cascades that detect pathogens, more examples of counterstrategies employed by pathogens also emerge. Degradation and inhibition of RNA sensors Since the discovery of the intracellular RNA sensing system, many immune evasion proteins that target RLRs or MAVS have been identified (see Fig. 1), mostly in viruses with an RNA genome, for which RIG‐I and/or MDA5 are the key PRRs during infection. Some viral proteases cleave RNA sensors, with several picornaviruses using their 3C protease to cleave RIG‐I, and the 2A protease to cleave MDA5.81-83 The leader protease Lpro from foot‐and‐mouth‐disease virus also cleaves Lpg2, a co‐factor for MDA5 activation.84 Some viruses modify RLRs with K48‐linked poly‐ubiquitin chains, diverting the RNA sensors for degradation by the cell's proteasome. Toscana virus non‐structural proteins and the rotavirus NSP1 protein cause the degradation of RIG‐I,85, 86 whereas West Nile virus NS1 targets both RIG‐I and MDA5.87 RIG‐I mRNA expression and translation can also be inhibited during viral infection: for instance, EBV expresses the virus‐encoded microRNA miR‐BART6‐3p, which targets RIG‐I mRNA,88 and hepatitis B virus induces the cellular microRNA miR146a, which inhibits RIG‐I expression.89 Even under conditions where the expression of RIG‐I and MDA5 is intact, the RNA sensors can be prevented from carrying out their signalling function by viral proteins that bind to them. The HSV‐1 protein UL37 interacts with RIG‐I and causes the de‐amidation of its helicase domain, which renders RIG‐I unable to sense RNA ligands.90 Another HSV‐1 protein, US11 inhibits RNA sensing by associating with the dsRNA binding protein PACT, which potentiates RNA‐induced responses.91, 92 PACT is also targeted by Influenza A virus NS1, the VP35 protein from Ebola virus and the 4a protein from Middle East respiratory syndrome coronavirus.93-95 Many of the PACT‐interacting proteins also bind dsRNA, so they probably shield the viral RNA from detection while at the same time inactivating PACT and RNA sensors. The activity of RIG‐I and MDA5 is tightly regulated in the cell: In the absence of infection, the CARD of the RNA sensors are kept in a phosphorylated state, and activation involves their dephosphorylation catalysed by protein phosphatase 1.96 RIG‐I activity is further enhanced by the assembly of K63‐linked poly‐ubiquitin chains catalysed by the E3 ubiquitin ligases tripartite motif containing 25 (TRIM25) and Riplet, which release RIG‐I from its autoinhibited state.97, 98 Given the importance of these post‐translational modifications, it is not surprising that many viruses have evolved ways of inhibiting these regulatory mechanisms. For instance, measles virus uses an elaborate signalling strategy involving the activation of the C‐type lectin DC‐SIGN to inhibit protein phosphatase 1, thus keeping the RLRs phosphorylated and inactive.99 The E3 ubiquitin ligase Riplet is inhibited by the multifunctional IAV NS1 protein100 and is cleaved by the NS3/4A protease from hepatitis C virus.101 Multiple viruses also inhibit TRIM25, including again IAV NS1, the SARS coronavirus N protein, the V protein from various paramyxoviruses, the large tegument protein BPLF1 from EBV and the E6 protein from human papillomavirus 16.102-107 The subgenomic flavivirus RNA from Dengue virus can also bind and inactivate TRIM25 in an RNA sequence‐specific manner.108 RIG‐I ubiquitylation by TRIM25 is also inhibited by the bacterial quorum sensing molecule cyclo(Phe‐Pro) from the opportunistic pathogen Vibrio vulnificus. Cyclo(Phe‐Pro) specifically binds to RIG‐I and prevents it from being ubiquitylated by TRIM25,109 possibly providing a link between bacterial infection and susceptibility to co‐infection with viruses. A multitude of viral immunomodulators prevent RIG‐I and MDA5 from interacting with its adaptor protein MAVS, so blocking the nucleation event that allows MAVS to form higher‐order signalling assemblies. Dengue virus NS3 binds 14‐3‐3ε to prevent the translocation of RIG‐I to MAVS.110 The interaction between RLRs and MAVS is also disrupted by the picornavirus 3Cpro proteases, the Z and N proteins of some arenaviruses, NS2 from respiratory syncytial virus, NS1 from IAV, NSP1 from rotavirus and US11 from HSV‐1.16, 86, 111-114 MAVS is also targeted directly by many viruses. MAVS‐interacting proteins include the metapneumovirus protein M2‐2,115 the NS4A proteins of Zika and Dengue viruses,116, 117 viral IRF1 from human herpesvirus 8118 and ORF9b from SARS coronavirus.119 MAVS is also diverted for proteasome‐mediated degradation by the hepatitis B virus X protein,120 and is cleaved by the hepatitis C virus protease NS3/4A, which releases it from the mitochondria and other intracellular membranes to disrupt signalling.121-124 The US9 protein from HSV‐1 causes MAVS to leak from the mitochondria by disrupting the mitochondrial membrane potential,125 and the IAV protein PB1‐F2 decreases mitochondrial membrane potential causing mitochondrial fragmentation.126, 127 Disrupting mitochondrial physiology is a common mechanism to block MAVS signalling. Infection with Dengue and Zika viruses causes mitochondrial elongation, which also blocks MAVS function.128 The sustained interferon production caused by MAVS signalling from the peroxisomes is inhibited by the MIA protein from human cytomegalovirus (hCMV) and the VP16 protein from HSV‐1.118, 129, 130 Although there are abundant examples of inhibition of RNA sensing by pathogens, and in particular viruses, there is one instance where a pathogen actually enhances signalling by RIG‐I and MDA5. The food‐borne pathogen Salmonella typhimurium uses its effector protein SopA, an E3 ubiquitin ligase, to ubiquitylate the host proteins TRIM56 and TRIM65, which in turn promote RIG‐I and MDA5 signalling.131, 132 This is an example of subversion, rather than evasion, of the interferon response, in line with the observation that the production of type I interferons can be advantageous to the pathogen, rather than the host, during some bacterial infections.64 Degradation and inhibition of DNA sensors Even though the cGAS/STING DNA sensing pathway was only discovered relatively recently, several viral and bacterial virulence factors that target this pathway have already been discovered, see Fig. 2. The nuclear DNA viruses hCMV, HSV‐1 and Kaposi's sarcoma‐associated herpesvirus all target several key DNA sensing factors to prevent the detection of their genomic DNA. HSV‐1 uses its ICP27 protein to inhibit STING.133 In addition, the E3 ubiquitin ligase ICP0 causes the degradation of IFI16 protein, and the virion host shutoff protein UL41 promotes the turnover of the mRNAs encoding IFI16 and cGAS.42, 134, 135 In addition, the HSV‐1 virion protein VP22 interacts with cGAS and inhibits its enzymatic activity136 and also interacts with AIM2 and blocks its oligomerization.137 HSV‐1 tegument protein UL37, which targets and deamidates RIG‐I, also deamidates cGAS, impairing cGAMP synthesis.138 The deployment of different virulence factors to target several components of the DNA sensing pathway may be necessary to block the pathway more efficiently, and/or to inhibit some non‐overlapping functions of cGAS and IFI16 which have been observed during herpesvirus infection.139 Analogously, several different hCMV proteins inhibit DNA sensing: pUL31 binds to cGAS and dissociates it from DNA,140 pUL83 inhibits both cGAS and IFI16,141-143 pUL82 inhibits STING translocation,144 IE2 causes STING degradation,145 and US9 inactivates both MAVS and STING.125 Furthermore, pUL83 binds AIM2 and facilitates the degradation of AIM2‐driven inflammasomes.146 A similar multi‐pronged approach has also been observed for the gammaherpesvirus Kaposi's sarcoma‐associated herpesvirus.147-150 STING is also inhibited by oncoproteins from the nuclear DNA viruses human adenovirus and human papillomavirus,151 and by vaccinia virus, a DNA virus that resides in the cytosol.152 Vaccinia virus also inhibits DNA‐PK, using its virulence factor C16 to bind the Ku70/Ku80 subunits of the DNA‐PK complex.153 The viral inhibitor of RIP activation (vIRA) from mouse CMV targets another proposed DNA sensor, DAI, to prevent the induction of programmed necrosis upon viral infection.154 Surprisingly, not only DNA viruses but also some RNA viruses have been found to antagonise STING – even though they do not produce DNA or cyclic dinucleotides during their replication cycle. It has been reported that STING can function in a cGAS‐independent manner during the detection of viral membrane fusion, for instance during infection with IAV.155 This non‐canonical STING signalling pathway is antagonized by the IAV fusion peptide.156 Flaviviruses, enveloped viruses with a positive‐stranded ssRNA genome, also inhibit STING‐dependent DNA sensing. Viral NS2B proteases encoded by Dengue virus, Zika virus, West Nile virus and Japanese encephalitis virus cleave human STING protein, but not its mouse orthologue.157, 158 The dengue virus NS2B co‐factor also targets cGAS for degradation.55 This prevents the activation of an innate immune response after the release of mitochondrial DNA, which occurs during Dengue virus infection,55, 159 highlighting the breadth of pathogen classes that can be detected directly or indirectly by the DNA sensing pathway (Fig. 2). While the production of type I interferons is not always an effective strategy to limit bacterial infections, the activation of STING by bacterial DNA or cyclic dinucleotides can also promote autophagy to clear bacteria from the infected cells. For this reason, some intracellular bacteria also inhibit STING.62 For instance, the Shigella effector protein IpaJ inhibits STING translocation from the endoplasmic reticulum to endoplasmic reticulum–Golgi intermediate compartment,38 and the Yersinia YopJ protein also blocks STING trafficking and causes its de‐ubiquitylation.160 Mycobacterium tuberculosis secretes the cyclic di‐nucleotide phosphodiesterase CdnP (also known as Rv2837c), which degrades cGAMP and bacterial cyclic dinucleotides, thus inhibiting both DNA‐ and cyclic‐dinucleotide‐induced STING activation.161 Group A streptococcus, Streptococcus pyogenes, subverts, rather than evades, STING signalling: it uses its M protein to activate STING, resulting in the production of the anti‐inflammatory cytokine interleukin‐10 downstream of type I interferon signalling.162 In this way, the bacterium exploits the reciprocal antagonism between the interferon response and inflammation, and shapes the immune response to favour the pathogen, rather than the host.
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Germinal Center B Cells Replace Their Antigen Receptors in Dark Zones and Fail Light Zone Entry when Immunoglobulin Gene Mutations are Damaging

Somatic hypermutation is important for the generation of high-affinity antibodies,
but this mutational process is also likely to negatively impact the functional integrity
of B cell receptors (BCRs). Stewart et al. find that germinal center B cells replace
surface BCRs in dark zones (DZ) and present evidence for a DZ checkpoint that prevents
the accumulation of clones with non-functional BCRs, thus facilitating selection in
the LZ.
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Cytokines in Sepsis: Potent Immunoregulators and Potential Therapeutic Targets—An Updated View

Cytokines in Sepsis: Potent Immunoregulators and Potential Therapeutic Targets—An Updated View | Immunology | Scoop.it
Sepsis and septic shock are among the leading causes of death in intensive care units worldwide. Numerous studies on their pathophysiology have revealed an imbalance in the inflammatory network leading to tissue damage, organ failure, and ultimately, death.
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Systems-level patterns emerge

Systems-level patterns emerge | Immunology | Scoop.it
Our knowledge of how the immune system changes with age has benefitted from a growing appreciation of the importance of systems-level analyses in humans. We are now beginning to uncover the global patterns of immune system development and decline in the young and the elderly.
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The immune system's fountain of youth | EurekAlert! Science News

The immune system's fountain of youth | EurekAlert! Science News | Immunology | Scoop.it
Helping the immune system clear away old cells in aging mice helped restore youthful characteristics.
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Calcium signalling in T cells

Calcium signalling in T cells | Immunology | Scoop.it
Regulated calcium signalling, in particular downstream of the T cell receptor, is crucial for many T cell effector functions. This Review provides an overview of the numerous membrane and organellar calcium-permeable channels that are coordinated to fine-tune T cell immunity.
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Tumor-educated B cells selectively promote breast cancer lymph node metastasis by HSPA4-targeting IgG

Tumor-educated B cells selectively promote breast cancer lymph node metastasis by HSPA4-targeting IgG | Immunology | Scoop.it
B cells facilitate breast cancer metastasis to lymph nodes through production of antibodies targeting a protein on the surface of cancer cells that stimulates tumor dissemination.
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Self-Awareness: Nucleic Acid–Driven Inflammation and the Type I Interferonopathies | Annual Review of Immunology

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Monoclonal antibodies and production of monoclonal antibodies

Monoclonal antibodies and production of monoclonal antibodies | Immunology | Scoop.it
Antibodies that arise from a single clone of cells (e.g., myeloma) are homogenous and are called monoclonal antibodies.Method of production of monoclonal.

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Pentraxins in Complement Activation and Regulation. - PubMed - NCBI

Pentraxins in Complement Activation and Regulation. - PubMed - NCBI | Immunology | Scoop.it
Front Immunol. 2018 Dec 19;9:3046. doi: 10.3389/fimmu.2018.03046. eCollection 2018.Review...
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Diversity and environmental adaptation of phagocytic cell metabolism - Davies - 2019 - Journal of Leukocyte Biology - Wiley Online Library

Journal of Leukocyte Biology considers manuscripts of original investigations focusing on the origins, developmental biology, biochemistry and functions of granulocytes, lymphocytes, mononuclear phagocytes, and other cells involved in host defense.
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Longitudinal single cell profiling of regulatory T cells identifies IL-33 as a driver of tumor immunosuppression

Regulatory T cells (Tregs) can impair anti-tumor immune responses and are associated with poor prognosis in multiple cancer types. Tregs in human tumors span diverse transcriptional states distinct from those of peripheral Tregs, but their contribution to tumor development remains unknown. Here, we used single cell RNA-Seq to longitudinally profile conventional CD4+ T cells (Tconv) and Tregs in a genetic mouse model of lung adenocarcinoma. Tissue-infiltrating and peripheral CD4+ T cells differed, highlighting divergent pathways of activation during tumorigenesis. Longitudinal shifts in Treg heterogeneity suggested increased terminal differentiation and stabilization of an effector phenotype over time. In particular, effector Tregs had enhanced expression of the interleukin 33 receptor ST2. Treg-specific deletion of ST2 reduced effector Tregs, increased infiltration of CD8+ T cells into tumors, and decreased tumor burden. Our study shows that ST2 plays a critical role in Treg-mediated immunosuppression in cancer, highlighting new potential paths for therapeutic intervention.
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Dendritic Cells | British Society for Immunology

Dendritic Cells | British Society for Immunology | Immunology | Scoop.it
Dendritic cells (DCs), named for their probing, ‘tree-like’ or dendritic shapes, are responsible for the initiation of adaptive immune responses and hence function as the ‘sentinels’ of the immune system.
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Coevolution of the coagulation and immune systems. - PubMed - NCBI

Coevolution of the coagulation and immune systems. - PubMed - NCBI | Immunology | Scoop.it
Inflamm Res. 2019 Jan 2. doi: 10.1007/s00011-018-01210-y.[Epub ahead of print] Review...
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T cell receptor–triggered nuclear actin network formation drives CD4+ T cell effector functions

T cell receptor–triggered nuclear actin network formation drives CD4+ T cell effector functions | Immunology | Scoop.it
T cell activation is regulated by numerous mechanisms upon T cell antigen receptor (TCR) engagement, including induction of specific cytokines by transcription factors like NF-κB and NFAT. Tsopoulidis et al . now show that TCR engagement causes rapid nuclear actin polymerization to create a dynamic actin filament network that is critical to CD4+ T cell effector functions. Nuclear actin filament polymerization involves the nuclear Arp2/3 complex that is induced by nuclear Ca2+ and regulated by N-Wasp and NIK. Specific inhibition of nuclear actin filament formation impairs T cell effector responses, including cytokine expression and CD4+ T cell help for antibody production. Together, these data reveal a role for nuclear actin filaments in driving CD4+ T cell effector functions.

T cell antigen receptor (TCR) signaling triggers selective cytokine expression to drive T cell proliferation and differentiation required for immune defense and surveillance. The nuclear signaling events responsible for specificity in cytokine gene expression upon T cell activation are largely unknown. Here, we uncover formation of a dynamic actin filament network in the nucleus that regulates cytokine expression for effector functions of CD4+ T lymphocytes. TCR engagement triggers the rapid and transient formation of a nuclear actin filament network via nuclear Arp2/3 complex, induced by elevated nuclear Ca2+ levels and regulated via N-Wasp and NIK. Specific interference with TCR-induced formation of nuclear actin filaments impairs production of effector cytokines and prevents generation of antigen-specific antibodies but does not interfere with immune synapse formation and cell proliferation. Ca2+-regulated actin polymerization in the nucleus allows CD4+ T cells the rapid conversion of TCR signals into effector functions required for T cell help.
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Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response

Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response | Immunology | Scoop.it
Melanoma cells release programmed death-ligand 1 (PD-L1) on the surface of circulating exosomes, suggesting a mechanism by which tumours could evade the immunesystem, and the potential application of exosomal PD-L1 to monitor patient responses to checkpoint therapies.
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IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy

IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy | Immunology | Scoop.it
Lionel Ivashkiv discusses new insight into the functions of IFNγ and summarizes our current understanding of IFNγ receptor signalling. In particular, the author focuses on recent studies on how IFNγ influences autoimmunity, immunometabolism, neurological diseases and cancer immunotherapy.
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Regulatory mechanisms in T cell receptor signalling

Regulatory mechanisms in T cell receptor signalling | Immunology | Scoop.it
This Review discusses the latest insights into the mechanisms regulating T cell receptor (TCR) signalling responses. In particular, the authors focus on how TCR signalling is regulated during thymocyte selection and during T cell homeostasis.
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