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Scooped by
Gilbert C FAURE
May 7, 2017 5:45 AM
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New findings in research funded by Morris Animal Foundation offer valuable insight on how to fight devil facial tumor disease (DFTD) that has resulted in a catastrophic decline in wild Tasmanian devils. Researchers have she
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Scooped by
Gilbert C FAURE
May 6, 2017 4:56 AM
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Dendritic cells are gatekeepers of Immunity and are crucial for the detection and initiation of Immunity against pathogens and foreign substances. Up to now dendritic cell subtypes were thought to develop from one common progenitor.
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Scooped by
Gilbert C FAURE
May 1, 2017 11:32 AM
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Scooped by
Gilbert C FAURE
April 30, 2017 3:49 AM
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In vivo and ex vivo imaging were used to investigate the function of galectin-3 (Gal-3) during the process of leukocyte recruitment to the inflamed microcirculation. The cremasteric microcirculation of wild-type (C57BL/6), Gal-3−/−, and CX3CR1gfp/+ mice were assessed by intravital microscopy after PBS, IL-1β, TNF-α, or recombinant Gal-3 treatment. These cellular responses were investigated further using flow-chamber assays, confocal microscopy, flow cytometry, PCR analysis, and proteome array. We show that mechanisms mediating leukocyte slow rolling and emigration are impaired in Gal-3−/− mice, which could be because of impaired expression of cell adhesion molecules and an altered cell surface glycoproteome. Local (intrascrotal) administration of recombinant Gal-3 to wild-type mice resulted in a dose-dependent reduction in rolling velocity associated with increased numbers of adherent and emigrated leukocytes, ∼50% of which were Ly6G+ neutrophils. Intrascrotal administration of Gal-3 to CX3CR1gfp/+ mice confirmed that approximately equal numbers of monocytes are also recruited in response to this lectin. Exogenous Gal-3 treatment was accompanied by increased proinflammatory cytokines and chemokines within the local tissue. In conclusion, this study unveils novel biology for both exogenous and endogenous Gal-3 in promoting leukocyte recruitment during acute inflammation.
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Scooped by
Gilbert C FAURE
April 29, 2017 1:07 AM
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The innate immune cells sense microbial infection and self-ligands, by pathogen recognition receptors (PRRs), such as toll-like receptors (TLRs) and regulatory receptors (RR) associated with immunoreceptor tyrosine-based activation motif (ITAM). Rapid activation and concerted action of PRRs signaling and feedback inhibitory mechanisms must be engaged to ensure the host defense functions and to prevent cytotoxicity associated with excessive activation. ITAM-associated RR can generate stimulatory or, paradoxically, inhibitory signals. The network of ITAM-associated RR, together with TLR-signaling pathways, are responsible for immunogenic or tolerogenic responses of macrophages and dendritic cells (DCs) to their microenvironment. In macrophages, TLR4 signaling is inhibited by low-avidity ligation of ITAM-associated receptors, while high-avidity ligation of ITAM-associated receptors results in potentiation of TLR4 signaling together with resistance to extracellular cytokine microenvironment signals. In contrast to macrophages, TLR7/9 signaling in plasmacytoid DC (pDCs) is inhibited by high-avidity ligation of ITAM-associated RR, while low-avidity ligation does not show any effect. Surprisingly, interference of ITAM-associated receptor signaling with TLR pathways has not been reported in conventional dendritic cells (cDCs). Here, we present an overview of molecular mechanisms acting at the crossroads of TLR and ITAM signaling pathways and address the question of how the high-avidity engagement of the ITAM-associated receptors in pDCs inhibits TLR7/9 signaling. Cellular context and spatio-temporal engagement of ITAM and TLR signaling pathways are responsible for different outcomes of macrophage versus pDC activation. While the cross-regulation of cytokine and TLR signaling, together with antigen presentation, are the principal functions of ITAM-associated RR in macrophages, the major role of these receptors in pDCs seems to be related to inhibition of cytokine production and reestablishment of a tolerogenic state following pDC activation. Pharmacologic targeting of TLR and ITAM signaling could be an attractive new therapeutic approach for treatment of chronic infections, cancer, and autoimmune and inflammatory diseases related to pDCs.
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Scooped by
Gilbert C FAURE
April 28, 2017 4:41 AM
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The heterogeneous group of diseases collectively termed cancer results not just from aberrant cellular proliferation but also from a lack of accompanying homeostatic cell death. Indeed, cancer cells regularly acquire resistance to programmed cell death, or apoptosis, which not only supports cancer progression but also leads to resistance to therapeutic agents. Thus, various approaches have been undertaken in order to induce apoptosis in tumor cells for therapeutic purposes. Here, we will focus our discussion on agents that directly affect the apoptotic machinery itself rather than on drugs that induce apoptosis in tumor cells indirectly, such as by DNA damage or kinase dependency inhibition. As the roles of the Bcl-2 family have been extensively studied and reviewed recently, we will focus in this review specifically on the inhibitor of apoptosis protein (IAP) family. IAPs are a disparate group of proteins that all contain a baculovirus IAP repeat domain, which is important for th
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Scooped by
Gilbert C FAURE
April 27, 2017 9:35 AM
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The BJC is owned by Cancer Research UK, a charity dedicated to understanding the causes, prevention and treatment of cancer and to making sure that the best new treatments reach patients in the clinic as quickly as possible. The journal reflects these aims. It was founded more than fifty years ago and, from the start, its far-sighted mission was to encourage communication of the very best cancer research from laboratories and clinics in all countries. The breadth of its coverage, its editorial independence and it consistent high standards, have made BJC one of the world's premier general cancer journals. Its increasing popularity is reflected by a steadily rising impact factor.
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Scooped by
Gilbert C FAURE
April 23, 2017 2:09 PM
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HLA-G is a natural tolerogenic molecule and has the following unique features: seven isoforms (HLA-G1 to HLA-G7), formation of disulfide-linked homodimers, and β2-microglobulin (β2m)-free forms. Interestingly, individuals null for the major isoform, HLA-G1, are healthy and expressed the α2 domain–deleted isoform, HLA-G2, which presumably compensates for HLA-G1 function. However, the molecular characteristics of HLA-G2 are largely unknown. In this study, we unexpectedly found that HLA-G2 naturally forms a β2m-free and nondisulfide-linked homodimer, which is in contrast to the disulfide-bonded β2m-associated HLA-G1 homodimer. Furthermore, single-particle analysis, using electron microscopy, revealed that the overall structure and domain organization of the HLA-G2 homodimer resemble those of the HLA class II heterodimer. The HLA-G2 homodimer binds to leukocyte Ig-like receptor B2 with slow dissociation and a significant avidity effect. These findings provide novel insights into leukocyte Ig-like receptor B2–mediated immune regulation by the HLA-G2 isoform, as well as the gene evolution of HLA classes.
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Scooped by
Gilbert C FAURE
April 21, 2017 2:56 PM
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ABSTRACT: IFN regulatory factor (IRF)3 plays a detrimental role in the cecal ligation and puncture (CLP) mouse model of sepsis. However, it is unclear which pathway activates IRF3 in this context. In this report, we investigate two pathways that activate IRF3: the Stimulator of Interferon Genes (STING) pathway (that senses cytosolic DNA) and the TIR-domain-containing adapter-inducing interferon-β (TRIF) pathway (that senses dsRNA and LPS via Toll-like receptor 3 and 4). Initially, we examine the impact of these pathways using a severe CLP model (∼90% mortality). Both STING-KO and TRIF-KO mice are protected from severe sepsis, exhibiting reduced mortality, disease score, hypothermia, and inflammatory cytokines relative to WT counterparts. STING/TRIF-DKO mice exhibit a similar phenotype to each of the single KO strains, suggesting that these pathways have an interrelated function. Subsequently, we examine the impact of these pathways using a moderate CLP model incorporating clinical treatments (Lactated Ringer Solution and antibiotics, ∼36% mortality). In this case, STING-KO mice show a similar phenotype to WT counterparts, while TRIF-KO mice show improved disease score and hypothermia. During sepsis, innate immune receptors recognize bacterial ligands and host-derived danger signals, including cell-free DNA released into the circulation. We show that IRF3 is activated in cultured macrophages treated with bacteria derived from the mouse cecum, dependent on TRIF, and in macrophages treated with mouse genomic DNA/Lipofectamine 2000, dependent on STING. Together, our data demonstrate that both the STING and TRIF pathways can promote sepsis pathogenesis; however, their contribution depends on the severity of the disease model. We show that bacteria are abundant in the peritoneum following both severe and moderate CLP, while cell-free DNA is more highly elevated in the serum following severe CLP compared with sham and moderate CLP. Hence, the presence of bacteria and cell-free DNA may explain the variable phenotypes in our severe CLP model (dependent on TRIF and STING) versus our moderate CLP model (dependent on TRIF only).
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Scooped by
Gilbert C FAURE
April 12, 2017 2:39 PM
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Cytotoxic CD8+ T cells either terminally differentiate and die or form a rapidly responding
population of memory T cells after pathogen clearance. Gray et al. define a temporal
model for how effector T cells lose memory cell potential through selective epigenetic
silencing of pro-memory genes.
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Scooped by
Gilbert C FAURE
April 10, 2017 1:57 PM
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Cellular and Molecular Immunology aims to report the dynamic progress being made in China and abroad in immunological research, and welcomes high-quality Research Articles, Reviews and Brief Reports across a broad range of topics including, but not limited to, clinical immunology, comparative immunology, immunobiology, immunogenetics, immunological techniques, immunopathology, immunopharmacology, infection immunology, neuroimmunology, transplantation immunology, tumor immunology, and veterinary immunology.
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Scooped by
Gilbert C FAURE
April 6, 2017 11:54 AM
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Dendritic cells (DCs) are crucial for mediating immune responses but, when deregulated, also contribute to immunological disorders, such as autoimmunity. The molecular mechanism underlying the function of DCs is incompletely understood. In this study, we have identified TANK-binding kinase 1 (TBK1), a master innate immune kinase, as an important regulator of DC function. DC-specific deletion of Tbk1 causes T cell activation and autoimmune symptoms and also enhances antitumor immunity in animal models of cancer immunotherapy. The TBK1-deficient DCs have up-regulated expression of co-stimulatory molecules and increased T cell–priming activity. We further demonstrate that TBK1 negatively regulates the induction of a subset of genes by type I interferon receptor (IFNAR). Deletion of IFNAR1 could largely prevent aberrant T cell activation and autoimmunity in DC-conditional Tbk1 knockout mice. These findings identify a DC-specific function of TBK1 in the maintenance of immune homeostasis and tolerance.
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Scooped by
Gilbert C FAURE
April 4, 2017 12:08 PM
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How and why the immune system becomes less effective with age are not well understood. Martinez-Jimenez et al. performed single-cell sequencing of CD4+ T cells in old and young mice of two species. In young mice, the gene expression program of early immune activation was tightly regulated and conserved between species. However, as mice aged, the expression of genes involved in pathways responding to immune cell stimulation was not as robust and exhibited increased cell-to-cell variability.
Science , this issue p. [1433][1]
[1]: /lookup/doi/10.1126/science.aah4115
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Scooped by
Gilbert C FAURE
May 7, 2017 5:37 AM
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Harvard University is issuing certificates for anybody who passes one or more of the same online courses that are also taken by incoming students prior to starting their Harvard Medical School curriculum and used by the institution's faculty to "flip" their classrooms.
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Scooped by
Gilbert C FAURE
May 6, 2017 4:54 AM
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Author summary The disease tuberculosis (TB) is caused by the microbe Mycobacterium tuberculosis (Mtb), and remains a major public health concern. More research is needed to understand the diverse immune responses against Mtb to develop better vaccines. Mouse Qa-1 and its human counterpart HLA-E are nonclassical MHC I molecules that can activate or inhibit immune responses in a variety of diseases. However, their role during the immune response to Mtb remains unknown. We found that Qa-1 can present Mtb peptides to activate CD8+ T effector cells during aerosol Mtb infection. Further, Mtb-infected mice that lacked Qa-1 (Qa-1-/-) had higher numbers of bacteria and died more often than infected mice that expressed Qa-1 (Qa-1+/+). The lack of Qa-1 results in over-activation of the immune response upon infection, which is less efficient in controlling Mtb. Using mice expressing different mutant forms of Qa-1, we showed that Qa-1 can regulate immune responses against Mtb through the interaction with inhibitory CD94/NKG2A receptors as well as the activation of regulatory CD8+ T cells. We believe our study sheds light on the diverse mechanisms at play in generating protective immune responses against Mtb and will inform future mouse and human studies.
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Scooped by
Gilbert C FAURE
May 1, 2017 11:22 AM
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Scooped by
Gilbert C FAURE
April 30, 2017 3:38 AM
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“Macrophages are real chatterboxes”
Facebook, Instagram, Twitter – nowadays, good social networking and communication is more important than ever. The immune system also resembles a large social network, as shown by Felix Meissner and his team in the Experimental System Immunology Research Group at the Max Planck Institute of Biochemistry in Martinsried. With the help of proteomics they deciphered the messages exchanged between immune cells responsible for protecting us against diseases. In doing so, they have discovered complex cellular communication structures and previously unknown connections between various cell types. Their findings were published in the journal Nature Immunology.
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Scooped by
Gilbert C FAURE
April 29, 2017 1:04 AM
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Loke and colleagues show that vitamin A is required for the conversion of interleukin 4 (IL-4)-activated monocyte-derived macrophages into macrophages with a tissue-resident phenotype in the peritoneal cavity and in S. mansoni-induced liver granulomas in mice.
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Suggested by
LIGHTING
April 27, 2017 2:32 PM
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DATE: May 3, 2017TIME: 8:00am PT, 11:00am ETThe natural immune responses that patients develop to their own tumors, as well as therapeutic regimens employing the latest anti-cancer
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Scooped by
Gilbert C FAURE
April 24, 2017 9:51 AM
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Single-cell RNA sequencing reveals new classes of human dendritic cells and monocytes; approach holds promise for elucidating other cell types in health and disease
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Scooped by
Gilbert C FAURE
April 21, 2017 2:58 PM
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Background: The neonatal innate immune system differs to microbial infection both quantitatively and
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Suggested by
Brian Shilling
April 13, 2017 11:16 AM
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How does the timing of isolation and cryopreservation following blood sample collection impact cell viability and functionality? Find out here.
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Scooped by
Gilbert C FAURE
April 12, 2017 1:49 PM
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Toll-like receptors (TLRs) play an important role in immune responses to pathogens by transducing signals in innate immune cells in response to microbial products. TLRs are also expressed on B cells, and TLR signaling in B cells contributes to antibody-mediated immunity and autoimmunity. The SYK tyrosine kinase is essential for signaling from the B cell antigen receptor (BCR), and thus for antibody responses. Surprisingly, we find that it is also required for B cell survival, proliferation, and cytokine secretion in response to signaling through several TLRs. We show that treatment of B cells with lipopolysaccharide, the ligand for TLR4, results in SYK activation and that this is dependent on the BCR. Furthermore, we show that B cells lacking the BCR are also defective in TLR-induced B cell activation. Our results demonstrate that TLR4 signals through two distinct pathways, one via the BCR leading to activation of SYK, ERK, and AKT and the other through MYD88 leading to activation of NF-κB.
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Scooped by
Gilbert C FAURE
April 7, 2017 2:37 AM
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Recognition of viral glycans by pattern recognition receptors (PRRs) in innate immunity contributes to antiviral immune responses. C-type lectin receptors (CLRs) are PRRs capable of sensing glycans present in viral pathogens to activate antiviral immune responses such as phagocytosis, antigen processing and presentation, and subsequent T cell activation. The ability of CLRs to elicit and shape adaptive immunity plays a critical role in the inhibition of viral spread within the host. However, certain viruses exploit CLRs for viral entry into host cells to avoid immune recognition. To block CLR interactions with viral glycoproteins, antiviral strategies may involve the use of multivalent glycan carrier systems. In this review, we describe the role of CLRs in antiviral immunity and we highlight their dual function in viral clearance and exploitation by viral pathogens.
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Scooped by
Gilbert C FAURE
April 5, 2017 11:26 AM
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National Academy of Sciences
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