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2. Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse.
- Author
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Choudhuri, Kaushik, Llodrá, Jaime, Roth, Eric W., Tsai, Jones, Gordo, Susana, Wucherpfennig, Kai W., Kam, Lance C., Stokes, David L., and Dustin, Michael L.
- Subjects
T-cell receptor genes ,SYNAPTIC vesicles ,IMMUNE system ,CELLULAR immunity ,ANTIGEN presenting cells ,LIGAND binding (Biochemistry) ,CELL membranes - Abstract
The recognition events that mediate adaptive cellular immunity and regulate antibody responses depend on intercellular contacts between T cells and antigen-presenting cells (APCs). T-cell signalling is initiated at these contacts when surface-expressed T-cell receptors (TCRs) recognize peptide fragments (antigens) of pathogens bound to major histocompatibility complex molecules (pMHC) on APCs. This, along with engagement of adhesion receptors, leads to the formation of a specialized junction between T cells and APCs, known as the immunological synapse, which mediates efficient delivery of effector molecules and intercellular signals across the synaptic cleft. T-cell recognition of pMHC and the adhesion ligand intercellular adhesion molecule-1 (ICAM-1) on supported planar bilayers recapitulates the domain organization of the immunological synapse, which is characterized by central accumulation of TCRs, adjacent to a secretory domain, both surrounded by an adhesive ring. Although accumulation of TCRs at the immunological synapse centre correlates with T-cell function, this domain is itself largely devoid of TCR signalling activity, and is characterized by an unexplained immobilization of TCR-pMHC complexes relative to the highly dynamic immunological synapse periphery. Here we show that centrally accumulated TCRs are located on the surface of extracellular microvesicles that bud at the immunological synapse centre. Tumour susceptibility gene 101 (TSG101) sorts TCRs for inclusion in microvesicles, whereas vacuolar protein sorting 4 (VPS4) mediates scission of microvesicles from the T-cell plasma membrane. The human immunodeficiency virus polyprotein Gag co-opts this process for budding of virus-like particles. B cells bearing cognate pMHC receive TCRs from T cells and initiate intracellular signals in response to isolated synaptic microvesicles. We conclude that the immunological synapse orchestrates TCR sorting and release in extracellular microvesicles. These microvesicles deliver transcellular signals across antigen-dependent synapses by engaging cognate pMHC on APCs. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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3. Structural basis of lentiviral subversion of a cellular protein degradation pathway.
- Author
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Schwefel, David, Groom, Harriet C. T., Boucherit, Virginie C., Christodoulou, Evangelos, Walker, Philip A., Stoye, Jonathan P., Bishop, Kate N., and Taylor, Ian A.
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LENTIVIRUSES ,PROTEOLYSIS ,CELLULAR signal transduction ,VIRUSES ,CELLULAR immunity ,HIV infections ,CYTOPROTECTION - Abstract
Lentiviruses contain accessory genes that have evolved to counteract the effects of host cellular defence proteins that inhibit productive infection. One such restriction factor, SAMHD1, inhibits human immunodeficiency virus (HIV)-1 infection of myeloid-lineage cells as well as resting CD4
+ T cells by reducing the cellular deoxynucleoside 5′-triphosphate (dNTP) concentration to a level at which the viral reverse transcriptase cannot function. In other lentiviruses, including HIV-2 and related simian immunodeficiency viruses (SIVs), SAMHD1 restriction is overcome by the action of viral accessory protein x (Vpx) or the related viral protein r (Vpr) that target and recruit SAMHD1 for proteasomal degradation. The molecular mechanism by which these viral proteins are able to usurp the host cell's ubiquitination machinery to destroy the cell's protection against these viruses has not been defined. Here we present the crystal structure of a ternary complex of Vpx with the human E3 ligase substrate adaptor DCAF1 and the carboxy-terminal region of human SAMHD1. Vpx is made up of a three-helical bundle stabilized by a zinc finger motif, and wraps tightly around the disc-shaped DCAF1 molecule to present a new molecular surface. This adapted surface is then able to recruit SAMHD1 via its C terminus, making it a competent substrate for the E3 ligase to mark for proteasomal degradation. The structure reported here provides a molecular description of how a lentiviral accessory protein is able to subvert the cell's normal protein degradation pathway to inactivate the cellular viral defence system. [ABSTRACT FROM AUTHOR]- Published
- 2014
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4. Stem cells: Immune response spurs cell switch.
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STEM cells ,CELLULAR immunity - Abstract
The article presents a study conducted by John Cooke and his colleagues at Stanford University in California regarding the efficient way to reprogram adult cells into embryonic-like stem cells by controlling cellular immune responses.
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- 2012
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5. Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells.
- Author
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Shalek, Alex K., Satija, Rahul, Adiconis, Xian, Gertner, Rona S., Gaublomme, Jellert T., Raychowdhury, Raktima, Schwartz, Schraga, Yosef, Nir, Malboeuf, Christine, Lu, Diana, Trombetta, John J., Gennert, Dave, Gnirke, Andreas, Goren, Alon, Hacohen, Nir, Levin, Joshua Z., Park, Hongkun, and Regev, Aviv
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GENE expression ,B cells ,RNA splicing ,NUCLEOTIDE sequence ,CELLULAR immunity ,LIPOPOLYSACCHARIDES ,LABORATORY mice - Abstract
Recent molecular studies have shown that, even when derived from a seemingly homogenous population, individual cells can exhibit substantial differences in gene expression, protein levels and phenotypic output, with important functional consequences. Existing studies of cellular heterogeneity, however, have typically measured only a few pre-selected RNAs or proteins simultaneously, because genomic profiling methods could not be applied to single cells until very recently. Here we use single-cell RNA sequencing to investigate heterogeneity in the response of mouse bone-marrow-derived dendritic cells (BMDCs) to lipopolysaccharide. We find extensive, and previously unobserved, bimodal variation in messenger RNA abundance and splicing patterns, which we validate by RNA-fluorescence in situ hybridization for select transcripts. In particular, hundreds of key immune genes are bimodally expressed across cells, surprisingly even for genes that are very highly expressed at the population average. Moreover, splicing patterns demonstrate previously unobserved levels of heterogeneity between cells. Some of the observed bimodality can be attributed to closely related, yet distinct, known maturity states of BMDCs; other portions reflect differences in the usage of key regulatory circuits. For example, we identify a module of 137 highly variable, yet co-regulated, antiviral response genes. Using cells from knockout mice, we show that variability in this module may be propagated through an interferon feedback circuit, involving the transcriptional regulators Stat2 and Irf7. Our study demonstrates the power and promise of single-cell genomics in uncovering functional diversity between cells and in deciphering cell states and circuits. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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6. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions.
- Author
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Yoshizaki, Ayumi, Miyagaki, Tomomitsu, DiLillo, David J., Matsushita, Takashi, Horikawa, Mayuka, Kountikov, Evgueni I., Spolski, Rosanne, Poe, Jonathan C., Leonard, Warren J., and Tedder, Thomas F.
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B cells ,T cells ,CELLULAR immunity ,INTERLEUKIN-21 ,CELLULAR control mechanisms ,AUTOIMMUNE diseases - Abstract
B cells regulate immune responses by producing antigen-specific antibodies. However, specific B-cell subsets can also negatively regulate T-cell immune responses, and have been termed regulatory B cells. Human and mouse regulatory B cells (B10 cells) with the ability to express the inhibitory cytokine interleukin-10 (IL-10) have been identified. Although rare, B10 cells are potent negative regulators of antigen-specific inflammation and T-cell-dependent autoimmune diseases in mice. How B10-cell IL-10 production and regulation of antigen-specific immune responses are controlled in vivo without inducing systemic immunosuppression is unknown. Using a mouse model for multiple sclerosis, here we show that B10-cell maturation into functional IL-10-secreting effector cells that inhibit in vivo autoimmune disease requires IL-21 and CD40-dependent cognate interactions with T cells. Moreover, the ex vivo provision of CD40 and IL-21 receptor signals can drive B10-cell development and expansion by four-million-fold, and generate B10 effector cells producing IL-10 that markedly inhibit disease symptoms when transferred into mice with established autoimmune disease. The ex vivo expansion and reinfusion of autologous B10 cells may provide a novel and effective in vivo treatment for severe autoimmune diseases that are resistant to current therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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7. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens.
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DePaolo, R. W., Abadie, V., Tang, F., Fehlner-Peach, H., Hall, J. A., Wang, W., Marietta, E. V., Kasarda, D. D., Waldmann, T. A., Murray, J. A., Semrad, C., Kupfer, S. S., Belkaid, Y., Guandalini, S., and Jabri, B.
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LYMPHOID tissue ,TRETINOIN ,ANTIGENS ,CELIAC disease ,IMMUNOLOGICAL adjuvants ,CELLULAR immunity - Abstract
Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses. Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients, retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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8. Programming the magnitude and persistence of antibody responses with innate immunity.
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Kasturi, Sudhir Pai, Skountzou, Ioanna, Albrecht, Randy A., Koutsonanos, Dimitrios, Tang Hua, Nakaya, Helder I., Ravindran, Rajesh, Stewart, Shelley, Alam, Munir, Kwissa, Marcin, Villinger, Francois, Murthy, Niren, Steel, John, Jacob, Joshy, Hogan, Robert J., García-Sastre, Adolfo, Compans, Richard, and Pulendran, Bali
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IMMUNOGLOBULINS ,VACCINES ,YELLOW fever ,DENDRITIC cells ,IMMUNOREGULATION ,CELLULAR immunity ,RESPIRATORY infections ,INFLUENZA A virus, H1N1 subtype - Abstract
Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendritic cells via Toll-like receptors (TLRs). For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed, activates dendritic cells via multiple TLRs to stimulate proinflammatory cytokines. Triggering specific combinations of TLRs in dendritic cells can induce synergistic production of cytokines, which results in enhanced T-cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that program such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles containing antigens plus a single TLR ligand. Consistent with this there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma-cell response relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated that there was early programming towards B-cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells, as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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9. Structural basis of oligomerization in the stalk region of dynamin-like MxA.
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Gao, Song, von der Malsburg, Alexander, Paeschke, Susann, Behlke, Joachim, Haller, Otto, Kochs, Georg, and Daumke, Oliver
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ORTHOMYXOVIRUSES ,GUANOSINE triphosphatase ,INTERFERONS ,PROTEINS ,CELLULAR immunity ,CELL membranes ,ENDOPLASMIC reticulum ,VIRAL replication ,GENETIC mutation - Abstract
The interferon-inducible dynamin-like myxovirus resistance protein 1 (MxA; also called MX1) GTPase is a key mediator of cell-autonomous innate immunity against pathogens such as influenza viruses. MxA partially localizes to COPI-positive membranes of the smooth endoplasmic reticulum–Golgi intermediate compartment. At the point of infection, it redistributes to sites of viral replication and promotes missorting of essential viral constituents. It has been proposed that the middle domain and the GTPase effector domain of dynamin-like GTPases constitute a stalk that mediates oligomerization and transmits conformational changes from the G domain to the target structure; however, the molecular architecture of this stalk has remained elusive. Here we report the crystal structure of the stalk of human MxA, which folds into a four-helical bundle. This structure tightly oligomerizes in the crystal in a criss-cross pattern involving three distinct interfaces and one loop. Mutations in each of these interaction sites interfere with native assembly, oligomerization, membrane binding and antiviral activity of MxA. On the basis of these results, we propose a structural model for dynamin oligomerization and stimulated GTP hydrolysis that is consistent with previous structural predictions and has functional implications for all members of the dynamin family. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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10. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity.
- Author
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Neill, Daniel R., See Heng Wong, Bellosi, Agustin, Flynn, Robin J., Daly, Maria, Langford, Theresa K. A., Bucks, Christine, Kane, Colleen M., Fallon, Padraic G., Pannell, Richard, Jolin, Helen E., and McKenzie, Andrew N. J.
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NIPPOSTRONGYLUS brasiliensis ,LEUCOCYTES ,CYTOKINES ,INTERLEUKINS ,CELLULAR immunity ,HELMINTHIASIS - Abstract
Innate immunity provides the first line of defence against invading pathogens and provides important cues for the development of adaptive immunity. Type-2 immunity—responsible for protective immune responses to helminth parasites and the underlying cause of the pathogenesis of allergic asthma—consists of responses dominated by the cardinal type-2 cytokines interleukin (IL)4, IL5 and IL13 (ref. 5). T cells are an important source of these cytokines in adaptive immune responses, but the innate cell sources remain to be comprehensively determined. Here, through the use of novel Il13-eGFP reporter mice, we present the identification and functional characterization of a new innate type-2 immune effector leukocyte that we have named the nuocyte. Nuocytes expand in vivo in response to the type-2-inducing cytokines IL25 and IL33, and represent the predominant early source of IL13 during helminth infection with Nippostrongylus brasiliensis. In the combined absence of IL25 and IL33 signalling, nuocytes fail to expand, resulting in a severe defect in worm expulsion that is rescued by the adoptive transfer of in vitro cultured wild-type, but not IL13-deficient, nuocytes. Thus, nuocytes represent a critically important innate effector cell in type-2 immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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11. TCR–peptide–MHC interactions in situ show accelerated kinetics and increased affinity.
- Author
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Huppa, Johannes B., Axmann, Markus, Mörtelmaier, Manuel A., Lillemeier, Björn F., Newell, Evan W., Brameshuber, Mario, Klein, Lawrence O., Schütz, Gerhard J., and Davis, Mark M.
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ANTIGENS ,IMMUNOGLOBULINS ,T cells ,LYMPHOCYTES ,IMMUNE response ,IMMUNOLOGY ,CELLULAR immunity ,T cell receptors ,MAJOR histocompatibility complex - Abstract
The recognition of foreign antigens by T lymphocytes is essential to most adaptive immune responses. It is driven by specific T-cell antigen receptors (TCRs) binding to antigenic peptide–major histocompatibility complex (pMHC) molecules on other cells. If productive, these interactions promote the formation of an immunological synapse. Here we show that synaptic TCR–pMHC binding dynamics differ significantly from TCR–pMHC binding in solution. We used single-molecule microscopy and fluorescence resonance energy transfer (FRET) between fluorescently tagged TCRs and their cognate pMHC ligands to measure the kinetics of TCR–pMHC binding in situ. When compared with solution measurements, the dissociation of this complex was increased significantly (4–12-fold). Disruption of actin polymers reversed this effect, indicating that cytoskeletal dynamics destabilize this interaction directly or indirectly. Nevertheless, TCR affinity for pMHC was significantly elevated as the result of a large (about 100-fold) increase in the association rate, a likely consequence of complementary molecular orientation and clustering. In helper T cells, the CD4 molecule has been proposed to bind cooperatively with the TCR to the same pMHC complex. However, CD4 blockade had no effect on the synaptic TCR affinity, nor did it destabilize TCR–pMHC complexes, indicating that the TCR binds pMHC independently of CD4. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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12. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells.
- Author
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Moro, Kazuyo, Yamada, Taketo, Tanabe, Masanobu, Takeuchi, Tsutomu, Ikawa, Tomokatsu, Kawamoto, Hiroshi, Furusawa, Jun-ichi, Ohtani, Masashi, Fujii, Hideki, and Koyasu, Shigeo
- Subjects
BACTERIA ,KILLER cells ,LYMPHOCYTES ,NATURAL immunity ,CELLULAR immunity ,B cells ,ADIPOSE tissues ,LYMPHOID tissue ,CYTOKINES ,HELMINTHIASIS - Abstract
Innate immune responses are important in combating various microbes during the early phases of infection. Natural killer (NK) cells are innate lymphocytes that, unlike T and B lymphocytes, do not express antigen receptors but rapidly exhibit cytotoxic activities against virus-infected cells and produce various cytokines. Here we report a new type of innate lymphocyte present in a novel lymphoid structure associated with adipose tissues in the peritoneal cavity. These cells do not express lineage (Lin) markers but do express c-Kit, Sca-1 (also known as Ly6a), IL7R and IL33R. Similar lymphoid clusters were found in both human and mouse mesentery and we term this tissue ‘FALC’ (fat-associated lymphoid cluster). FALC Lin
- c-Kit+ Sca-1+ cells are distinct from lymphoid progenitors and lymphoid tissue inducer cells. These cells proliferate in response to IL2 and produce large amounts of TH 2 cytokines such as IL5, IL6 and IL13. IL5 and IL6 regulate B-cell antibody production and self-renewal of B1 cells. Indeed, FALC Lin- c-Kit+ Sca-1+ cells support the self-renewal of B1 cells and enhance IgA production. IL5 and IL13 mediate allergic inflammation and protection against helminth infection. After helminth infection and in response to IL33, FALC Lin- c-Kit+ Sca-1+ cells produce large amounts of IL13, which leads to goblet cell hyperplasia—a critical step for helminth expulsion. In mice devoid of FALC Lin- c-Kit+ Sca-1+ cells, such goblet cell hyperplasia was not induced. Thus, FALC Lin- c-Kit+ Sca-1+ cells are TH 2-type innate lymphocytes, and we propose that these cells be called ‘natural helper cells’. [ABSTRACT FROM AUTHOR]- Published
- 2010
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13. Materials engineering for immunomodulation.
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Hubbell, Jeffrey A., Thomas, Susan N., and Swartz, Melody A.
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IMMUNOGLOBULINS ,IMMUNOREGULATION ,T cells ,LYMPHOCYTES ,IMMUNOLOGICAL adjuvants ,CELLULAR immunity ,IMMUNITY ,IMMUNOMODULATORS ,CYTOKINES - Abstract
The engineering of materials that can modulate the immune system is an emerging field that is developing alongside immunology. For therapeutic ends such as vaccine development, materials are now being engineered to deliver antigens through specific intracellular pathways, allowing better control of the way in which antigens are presented to one of the key types of immune cell, T cells. Materials are also being designed as adjuvants, to mimic specific 'danger' signals in order to manipulate the resultant cytokine environment, which influences how antigens are interpreted by T cells. In addition to offering the potential for medical advances, immunomodulatory materials can form well-defined model systems, helping to provide new insight into basic immunobiology. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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14. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses.
- Author
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Yanai, Hideyuki, Ban, Tatsuma, Wang, ZhiChao, Choi, Myoung Kwon, Kawamura, Takeshi, Negishi, Hideo, Nakasato, Makoto, Lu, Yan, Hangai, Sho, Koshiba, Ryuji, Savitsky, David, Ronfani, Lorenza, Akira, Shizuo, Bianchi, Marco E., Honda, Kenya, Tamura, Tomohiko, Kodama, Tatsuhiko, and Taniguchi, Tadatsugu
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NUCLEIC acids ,IMMUNE response ,GLYCOPROTEINS ,LYMPHOKINES ,CELL receptors ,TRANSCRIPTION factors ,CELLULAR immunity ,PROTEINS ,RNA ,INTERFERONS - Abstract
The activation of innate immune responses by nucleic acids is crucial to protective and pathological immunities and is mediated by the transmembrane Toll-like receptors (TLRs) and cytosolic receptors. However, it remains unknown whether a mechanism exists that integrates these nucleic-acid-sensing systems. Here we show that high-mobility group box (HMGB) proteins 1, 2 and 3 function as universal sentinels for nucleic acids. HMGBs bind to all immunogenic nucleic acids examined with a correlation between affinity and immunogenic potential. Hmgb1
-/- and Hmgb2-/- mouse cells are defective in type-I interferon and inflammatory cytokine induction by DNA or RNA targeted to activate the cytosolic nucleic-acid-sensing receptors; cells in which the expression of all three HMGBs is suppressed show a more profound defect, accompanied by impaired activation of the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor (NF)-κB. The absence of HMGBs also severely impairs the activation of TLR3, TLR7 and TLR9 by their cognate nucleic acids. Our results therefore indicate a hierarchy in the nucleic-acid-mediated activation of immune responses, wherein the selective activation of nucleic-acid-sensing receptors is contingent on the more promiscuous sensing of nucleic acids by HMGBs. These findings may have implications for understanding the evolution of the innate immune system and for the treatment of immunological disorders. [ABSTRACT FROM AUTHOR]- Published
- 2009
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15. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms.
- Author
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Sanada, Masashi, Suzuki, Takahiro, Shih, Lee-Yung, Otsu, Makoto, Kato, Motohiro, Yamazaki, Satoshi, Tamura, Azusa, Honda, Hiroaki, Sakata-Yanagimoto, Mamiko, Kumano, Keiki, Oda, Hideaki, Yamagata, Tetsuya, Takita, Junko, Gotoh, Noriko, Nakazaki, Kumi, Kawamata, Norihiko, Onodera, Masafumi, Nobuyoshi, Masaharu, Hayashi, Yasuhide, and Harada, Hiroshi
- Subjects
TUMOR suppressor genes ,CANCER genetics ,LOSS of heterozygosity ,LIGASES ,CARCINOGENESIS ,PROTEIN-tyrosine kinases ,CBL proteins ,GERM cell tumors ,ONCOGENIC viruses ,CANCER genes ,CELLULAR immunity - Abstract
Acquired uniparental disomy (aUPD) is a common feature of cancer genomes, leading to loss of heterozygosity. aUPD is associated not only with loss-of-function mutations of tumour suppressor genes, but also with gain-of-function mutations of proto-oncogenes. Here we show unique gain-of-function mutations of the C-CBL (also known as CBL) tumour suppressor that are tightly associated with aUPD of the 11q arm in myeloid neoplasms showing myeloproliferative features. The C-CBL proto-oncogene, a cellular homologue of v-Cbl, encodes an E3 ubiquitin ligase and negatively regulates signal transduction of tyrosine kinases. Homozygous C-CBL mutations were found in most 11q-aUPD-positive myeloid malignancies. Although the C-CBL mutations were oncogenic in NIH3T3 cells, c-Cbl was shown to functionally and genetically act as a tumour suppressor. C-CBL mutants did not have E3 ubiquitin ligase activity, but inhibited that of wild-type C-CBL and CBL-B (also known as CBLB), leading to prolonged activation of tyrosine kinases after cytokine stimulation. c-Cbl
-/- haematopoietic stem/progenitor cells (HSPCs) showed enhanced sensitivity to a variety of cytokines compared to c-Cbl+/+ HSPCs, and transduction of C-CBL mutants into c-Cbl-/- HSPCs further augmented their sensitivities to a broader spectrum of cytokines, including stem-cell factor (SCF, also known as KITLG), thrombopoietin (TPO, also known as THPO), IL3 and FLT3 ligand (FLT3LG), indicating the presence of a gain-of-function that could not be attributed to a simple loss-of-function. The gain-of-function effects of C-CBL mutants on cytokine sensitivity of HSPCs largely disappeared in a c-Cbl+/+ background or by co-transduction of wild-type C-CBL, which suggests the pathogenic importance of loss of wild-type C-CBL alleles found in most cases of C-CBL-mutated myeloid neoplasms. Our findings provide a new insight into a role of gain-of-function mutations of a tumour suppressor associated with aUPD in the pathogenesis of some myeloid cancer subsets. [ABSTRACT FROM AUTHOR]- Published
- 2009
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16. The AP-1 transcription factor Batf controls TH17 differentiation.
- Author
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Schraml, Barbara U., Hildner, Kai, Ise, Wataru, Wan-Ling Lee, Smith, Whitney A.-E., Solomon, Ben, Sahota, Gurmukh, Sim, Julia, Mukasa, Ryuta, Cemerski, Saso, Hatton, Robin D., Stormo, Gary D., Weaver, Casey T., Russell, John H., Murphy, Theresa L., and Murphy, Kenneth M.
- Subjects
TRANSCRIPTION factors ,NF-kappa B ,NUCLEAR receptors (Biochemistry) ,LEUCINE zippers ,HELIX-loop-helix motifs ,DNA-binding proteins ,CELLULAR immunity ,ENCEPHALOMYELITIS ,CYTOKINES - Abstract
Activator protein 1 (AP-1, also known as JUN) transcription factors are dimers of JUN, FOS, MAF and activating transcription factor (ATF) family proteins characterized by basic region and leucine zipper domains. Many AP-1 proteins contain defined transcriptional activation domains, but BATF and the closely related BATF3 (refs 2, 3) contain only a basic region and leucine zipper, and are considered to be inhibitors of AP-1 activity. Here we show that Batf is required for the differentiation of IL17-producing T helper (T
H 17) cells. TH 17 cells comprise a CD4+ T-cell subset that coordinates inflammatory responses in host defence but is pathogenic in autoimmunity. Batf-/- mice have normal TH 1 and TH 2 differentiation, but show a defect in TH 17 differentiation, and are resistant to experimental autoimmune encephalomyelitis. Batf-/- T cells fail to induce known factors required for TH 17 differentiation, such as RORγt (encoded by Rorc) and the cytokine IL21 (refs 14–17). Neither the addition of IL21 nor the overexpression of RORγt fully restores IL17 production in Batf-/- T cells. The Il17 promoter is BATF-responsive, and after TH 17 differentiation, BATF binds conserved intergenic elements in the Il17a–Il17f locus and to the Il17, Il21 and Il22 (ref. 18) promoters. These results demonstrate that the AP-1 protein BATF has a critical role in TH 17 differentiation. [ABSTRACT FROM AUTHOR]- Published
- 2009
- Full Text
- View/download PDF
17. Frequent inactivation of A20 in B-cell lymphomas.
- Author
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Kato, Motohiro, Sanada, Masashi, Kato, Itaru, Sato, Yasuharu, Takita, Junko, Takeuchi, Kengo, Niwa, Akira, Chen, Yuyan, Nakazaki, Kumi, Nomoto, Junko, Asakura, Yoshitaka, Muto, Satsuki, Tamura, Azusa, Iio, Mitsuru, Akatsuka, Yoshiki, Hayashi, Yasuhide, Mori, Hiraku, Igarashi, Takashi, Kurokawa, Mineo, and Chiba, Shigeru
- Subjects
B cell lymphoma ,NECROSIS ,CELLULAR immunity ,HODGKIN'S disease ,HISTOPATHOLOGY ,AUTOIMMUNE diseases ,GENOMES ,LABORATORY mice ,GENETICS ,DISEASE risk factors - Abstract
A20 is a negative regulator of the NF-κB pathway and was initially identified as being rapidly induced after tumour-necrosis factor-α stimulation. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-κB in response to a variety of external stimuli; recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk. However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin’s lymphoma of nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma-derived cell line with no functional A20 alleles, wild-type A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-κB activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-κB activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-κB activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-κB caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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18. T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance.
- Author
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Pesu, Marko, Watford, Wendy T., Lai Wei, Lili Xu, Fuss, Ivan, Strober, Warren, Andersson, John, Shevach, Ethan M., Quezado, Martha, Bouladoux, Nicolas, Roebroek, Anton, Belkaid, Yasmine, Creemers, John, and O'Shea, John J.
- Subjects
T cells ,CYTOKINES ,TRANSFORMING growth factors ,IMMUNOMODULATORS ,IMMUNE response ,CELLULAR immunity - Abstract
Furin is one of seven proprotein convertase family members that promote proteolytic maturation of proproteins. It is induced in activated T cells and is reported to process a variety of substrates including the anti-inflammatory cytokine transforming growth factor (TGF)-β1 (refs 2–4), but the non-redundant functions of furin versus other proprotein convertases in T cells are unclear. Here we show that conditional deletion of furin in T cells allowed for normal T-cell development but impaired the function of regulatory and effector T cells, which produced less TGF-β1. Furin-deficient T regulatory (T
reg ) cells were less protective in a T-cell transfer colitis model and failed to induce Foxp3 in normal T cells. Additionally, furin-deficient effector cells were inherently over-active and were resistant to suppressive activity of wild-type Treg cells. Thus, our results indicate that furin is indispensable in maintaining peripheral tolerance, which is due, at least in part, to its non-redundant, essential function in regulating TGF-β1 production. Targeting furin has emerged as a strategy in malignant and infectious disease. Our results suggest that inhibiting furin might activate immune responses, but may result in a breakdown in peripheral tolerance. [ABSTRACT FROM AUTHOR]- Published
- 2008
- Full Text
- View/download PDF
19. Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex.
- Author
-
Yong Gong, Peng Cao, Hong-jun Yu, and Tao Jiang
- Subjects
NERVOUS system ,TYROSINE ,CYTOKINES ,NERVE tissue proteins ,CELLULAR immunity ,IMMUNOREGULATION ,GROWTH factors ,PROTEIN-tyrosine kinases ,FOCAL adhesion kinase - Abstract
Neurotrophins (NTs) are important regulators for the survival, differentiation and maintenance of different peripheral and central neurons. NTs bind to two distinct classes of glycosylated receptor: the p75 neurotrophin receptor (p75
NTR ) and tyrosine kinase receptors (Trks). Whereas p75NTR binds to all NTs, the Trk subtypes are specific for each NT. The question of whether NTs stimulate p75NTR by inducing receptor homodimerization is still under debate. Here we report the 2.6-Å resolution crystal structure of neurotrophin-3 (NT-3) complexed to the ectodomain of glycosylated p75NTR . In contrast to the previously reported asymmetric complex structure, which contains a dimer of nerve growth factor (NGF) bound to a single ectodomain of deglycosylated p75NTR (ref. 3), we show that NT-3 forms a central homodimer around which two glycosylated p75NTR molecules bind symmetrically. Symmetrical binding occurs along the NT-3 interfaces, resulting in a 2:2 ligand–receptor cluster. A comparison of the symmetrical and asymmetric structures reveals significant differences in ligand–receptor interactions and p75NTR conformations. Biochemical experiments indicate that both NT-3 and NGF bind to p75NTR with 2:2 stoichiometry in solution, whereas the 2:1 complexes are the result of artificial deglycosylation. We therefore propose that the symmetrical 2:2 complex reflects a native state of p75NTR activation at the cell surface. These results provide a model for NTs-p75NTR recognition and signal generation, as well as insights into coordination between p75NTR and Trks. [ABSTRACT FROM AUTHOR]- Published
- 2008
- Full Text
- View/download PDF
20. The ground state of embryonic stem cell self-renewal.
- Author
-
Qi-Long Ying, Wray, Jason, Nichols, Jennifer, Batlle-Morera, Laura, Doble, Bradley, Woodgett, James, Cohen, Philip, and Smith, Austin
- Subjects
EMBRYONIC stem cells ,STEM cells ,CELLS ,HYBRID embryos ,BLASTODERM ,CYTOKINES ,CELLULAR immunity ,IMMUNOREGULATION ,GROWTH factors ,ENDOCRINE glands - Abstract
In the three decades since pluripotent mouse embryonic stem (ES) cells were first described they have been derived and maintained by using various empirical combinations of feeder cells, conditioned media, cytokines, growth factors, hormones, fetal calf serum, and serum extracts. Consequently ES-cell self-renewal is generally considered to be dependent on multifactorial stimulation of dedicated transcriptional circuitries, pre-eminent among which is the activation of STAT3 by cytokines (ref. 8). Here we show, however, that extrinsic stimuli are dispensable for the derivation, propagation and pluripotency of ES cells. Self-renewal is enabled by the elimination of differentiation-inducing signalling from mitogen-activated protein kinase. Additional inhibition of glycogen synthase kinase 3 consolidates biosynthetic capacity and suppresses residual differentiation. Complete bypass of cytokine signalling is confirmed by isolating ES cells genetically devoid of STAT3. These findings reveal that ES cells have an innate programme for self-replication that does not require extrinsic instruction. This property may account for their latent tumorigenicity. The delineation of minimal requirements for self-renewal now provides a defined platform for the precise description and dissection of the pluripotent state. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
21. Imaging of Rab5 activity identifies essential regulators for phagosome maturation.
- Author
-
Kitano, Masahiro, Nakaya, Michio, Nakamura, Takeshi, Nagata, Shigekazu, and Matsuda, Michiyuki
- Subjects
IMMUNE response ,CELLULAR immunity ,PHAGOCYTOSIS ,ANTIGEN-antibody reactions ,PHYSIOLOGICAL control systems ,CELLULAR control mechanisms ,BIOLOGICAL systems ,BIOSYNTHESIS ,GENETIC markers ,BIOCHEMISTRY - Abstract
Efficient phagocytosis of apoptotic cells is crucial for tissue homeostasis and the immune response. Rab5 is known as a key regulator of the early endocytic pathway and we have recently shown that Rab5 is also implicated in apoptotic cell engulfment; however, the precise spatio-temporal dynamics of Rab5 activity remain unknown. Here, using a newly developed fluorescence resonance energy transfer biosensor, we describe a change in Rab5 activity during the engulfment of apoptotic thymocytes. Rab5 activity on phagosome membranes began to increase on disassembly of the actin coat encapsulating phagosomes. Rab5 activation was either continuous or repetitive for up to 10 min, but it ended before the collapse of engulfed apoptotic cells. Expression of a dominant-negative mutant of Rab5 delayed this collapse of apoptotic thymocytes, showing a role for Rab5 in phagosome maturation. Disruption of microtubules with nocodazole inhibited Rab5 activation on the phagosome membrane without perturbing the engulfment of apoptotic cells. Furthermore, we found that Gapex-5 is the guanine nucleotide exchange factor essential for Rab5 activation during the engulfment of apoptotic cells. Gapex-5 was bound to a microtubule-tip-associating protein, EB1, whose depletion inhibited Rab5 activation during phagocytosis. We therefore propose a mechanistic model in which the recruitment of Gapex-5 to phagosomes through the microtubule network induces the transient Rab5 activation. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
22. TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function.
- Author
-
Liang Zhou, Lopes, Jared E., Chong, Mark M. W., Ivanov, Ivaylo I., Min, Roy, Victora, Gabriel D., Yuelei Shen, Du, Jianguang, Rubtsov, Yuri P., Rudensky, Alexander Y., Ziegler, Steven F., and Littman, Dan R.
- Subjects
T cells ,CELLULAR immunity ,CELL differentiation ,CELL-mediated lympholysis ,SUPPRESSOR cells ,IMMUNE response ,IMMUNOLOGY ,ANTIGEN-antibody reactions ,IMMUNOLOGICAL tolerance ,IMMUNE recognition - Abstract
T helper cells that produce IL-17 (T
H 17 cells) promote autoimmunity in mice and have been implicated in the pathogenesis of human inflammatory diseases. At mucosal surfaces, TH 17 cells are thought to protect the host from infection, whereas regulatory T (Treg ) cells control immune responses and inflammation triggered by the resident microflora. Differentiation of both cell types requires transforming growth factor-β (TGF-β), but depends on distinct transcription factors: RORγt (encoded by Rorc(γt)) for TH 17 cells and Foxp3 for Treg cells. How TGF-β regulates the differentiation of T cells with opposing activities has been perplexing. Here we demonstrate that, together with pro-inflammatory cytokines, TGF-β orchestrates TH 17 cell differentiation in a concentration-dependent manner. At low concentrations, TGF-β synergizes with interleukin (IL)-6 and IL-21 (refs 9–11) to promote IL-23 receptor (Il23r) expression, favouring TH 17 cell differentiation. High concentrations of TGF-β repress IL23r expression and favour Foxp3+ Treg cells. RORγt and Foxp3 are co-expressed in naive CD4+ T cells exposed to TGF-β and in a subset of T cells in the small intestinal lamina propria of the mouse. In vitro, TGF-β-induced Foxp3 inhibits RORγt function, at least in part through their interaction. Accordingly, lamina propria T cells that co-express both transcription factors produce less IL-17 (also known as IL-17a) than those that express RORγt alone. IL-6, IL-21 and IL-23 relieve Foxp3-mediated inhibition of RORγt, thereby promoting TH 17 cell differentiation. Therefore, the decision of antigen-stimulated cells to differentiate into either TH 17 or Treg cells depends on the cytokine-regulated balance of RORγt and Foxp3. [ABSTRACT FROM AUTHOR]- Published
- 2008
- Full Text
- View/download PDF
23. Memory CD4 T cells emerge from effector T-cell progenitors.
- Author
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Harrington, Laurie E., Janowski, Karen M., Oliver, James R., Zajac, Allan J., and Weaver, Casey T.
- Subjects
CELLULAR immunity ,T cells ,CELL differentiation ,MEMORY ,ANTIGENS ,VACCINATION ,PATHOGENIC microorganisms ,THERAPEUTICS ,INFECTION - Abstract
A hallmark of adaptive immunity is the generation of memory T cells that confer long-lived, antigen-specific protection against repeat challenges by pathogens. Understanding the mechanisms by which memory T cells arise is important for rational vaccination strategies and improved therapeutic interventions for chronic infections and autoimmune disorders. The large clonal expansion of CD8 T cells in response to some infections has made the development of CD8 T-cell memory more amenable to study, giving rise to a model of memory cell differentiation in which a fraction of fully competent effector T cells transition into long-lived memory T cells. Delineation of CD4 T-cell memory development has proved more difficult as a result of limitations on tracking the smaller populations of CD4 effector T cells generated during a pathogenic challenge, complicating efforts to determine whether CD4 memory T cells are direct descendants of effector T cells or whether they develop by alternative pathways. Here, using two complementary cytokine reporter mouse models to identify interferon (IFN)-γ-positive effector T cells and track their fate, we show that the lineage relationship between effector and memory CD4 T cells resembles that for CD8 T cells responding to the same pathogen. We find that, in parallel with effector CD8 T cells, IFN-γ-positive effector CD4 T cells give rise to long-lived memory T cells capable of anamnestic responses to antigenic rechallenge. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
24. Herpesvirus latency confers symbiotic protection from bacterial infection.
- Author
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Barton, Erik S., White, Douglas W., Cathelyn, Jason S., Brett-McClellan, Kelly A., Engle, Michael, Diamond, Michael S., Miller, Virginia L., and Virgin, Herbert W.
- Subjects
HERPESVIRUSES ,DNA viruses ,BACTERIAL diseases ,PATHOGENIC microorganisms ,CELLULAR immunity ,ENTEROBACTERIACEAE - Abstract
All humans become infected with multiple herpesviruses during childhood. After clearance of acute infection, herpesviruses enter a dormant state known as latency. Latency persists for the life of the host and is presumed to be parasitic, as it leaves the individual at risk for subsequent viral reactivation and disease. Here we show that herpesvirus latency also confers a surprising benefit to the host. Mice latently infected with either murine gammaherpesvirus 68 or murine cytomegalovirus, which are genetically highly similar to the human pathogens Epstein–Barr virus and human cytomegalovirus, respectively, are resistant to infection with the bacterial pathogens Listeria monocytogenes and Yersinia pestis. Latency-induced protection is not antigen specific but involves prolonged production of the antiviral cytokine interferon-γ and systemic activation of macrophages. Latency thereby upregulates the basal activation state of innate immunity against subsequent infections. We speculate that herpesvirus latency may also sculpt the immune response to self and environmental antigens through establishment of a polarized cytokine environment. Thus, whereas the immune evasion capabilities and lifelong persistence of herpesviruses are commonly viewed as solely pathogenic, our data suggest that latency is a symbiotic relationship with immune benefits for the host. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
25. APOBEC3 inhibits mouse mammary tumour virus replication in vivo.
- Author
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Okeoma, Chioma M., Lovsin, Nika, Peterlin, B. Matija, and Ross, Susan R.
- Subjects
GENOMES ,GENES ,CELLULAR immunity ,HIV ,HIV antibodies ,VIRAL genetics - Abstract
Genomes of all mammals encode apobec3 genes, which are thought to have a function in intrinsic cellular immunity to several viruses including human immunodeficiency virus type 1 (HIV-1). APOBEC3 (A3) proteins are packaged into virions and inhibit retroviral replication in newly infected cells, at least in part by deaminating cytidines on the negative strand DNA intermediates. However, the role of A3 in innate resistance to mouse retroviruses is not understood. Here we show that A3 functions during retroviral infection in vivo and provides partial protection to mice against infection with mouse mammary tumour virus (MMTV). Both mouse A3 and human A3G proteins interacted with the MMTV nucleocapsid in an RNA-dependent fashion and were packaged into virions. In addition, mouse A3-containing and human A3G-containing virions showed a marked decrease in titre. Last, A3
-/- mice were more susceptible to MMTV infection, because virus spread was more rapid and extensive than in their wild-type littermates. [ABSTRACT FROM AUTHOR]- Published
- 2007
- Full Text
- View/download PDF
26. Pathogenesis and therapy of psoriasis.
- Author
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Lowes, Michelle A., Bowcock, Anne M., and Krueger, James G.
- Subjects
SKIN diseases ,PSORIASIS treatment ,DISEASE complications ,KERATINOCYTES ,CELLULAR immunity ,CHEMOKINES - Abstract
Psoriasis is one of the most common human skin diseases and is considered to have key genetic underpinnings. It is characterized by excessive growth and aberrant differentiation of keratinocytes, but is fully reversible with appropriate therapy. The trigger of the keratinocyte response is thought to be activation of the cellular immune system, with T cells, dendritic cells and various immune-related cytokines and chemokines implicated in pathogenesis. The newest therapies for psoriasis target its immune components and may predict potential treatments for other inflammatory human diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
27. Early events in the thymus affect the balance of effector and regulatory T cells.
- Author
-
Pennington, Daniel J., Silva-Santos, Bruno, Silberzahn, Tobias, Escórcio-Correia, Mónica, Woodward, Martin J., Roberts, Scott J., Smith, Adrian L., Dyson, P. Julian, and Hayday, Adrian C.
- Subjects
CELLULAR immunity ,IMMUNOPATHOLOGY ,THYMUS ,T cells ,TRANSCRIPTION factors ,CELL receptors - Abstract
In cellular immunology the critical balance between effector and regulatory mechanisms is highlighted by serious immunopathologies attributable to mutations in Foxp3, a transcription factor required for a major subset of regulatory T (T
r ) cells. Thus, many studies have focused on the developmental origin of Tr cells, with the prevailing view that they emerge in the thymus from late-stage T-cell progenitors whose T-cell receptors (TCRs) engage high affinity (agonist) ligands. This study questions the completeness of that interpretation. Here we show that without any obvious effect on TCR-mediated selection, the normal differentiation of mouse γδ T cells into potent cytolytic and interferon-γ-secreting effector cells is switched towards an aggregate regulatory phenotype by limiting the capacity of CD4+ CD8+ T-cell progenitors to influence in trans early γδ cell progenitors. Unexpectedly, we found that the propensity of early TCR-αβ+ progenitors to differentiate into Foxp3+ Tr cells is also regulated in trans by CD4+ CD8+ T-cell progenitor cells, before agonist selection. [ABSTRACT FROM AUTHOR]- Published
- 2006
- Full Text
- View/download PDF
28. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity.
- Author
-
Gross, Olaf, Gewies, Andreas, Finger, Katrin, Schäfer, Martin, Sparwasser, Tim, Peschel, Christian, Förster, Irmgard, and Ruland, Jürgen
- Subjects
MYCOSES ,IMMUNODEFICIENCY ,AIDS ,IMMUNE response ,TYROSINE ,CELLULAR immunity - Abstract
Fungal infections are increasing worldwide due to the marked rise in immunodeficiencies including AIDS; however, immune responses to fungi are poorly understood. Dectin-1 is the major mammalian pattern recognition receptor for the fungal component zymosan. Dectin-1 represents the prototype of innate non-Toll-like receptors (TLRs) containing immunoreceptor tyrosine-based activation motifs (ITAMs) related to those of adaptive antigen receptors. Here we identify Card9 as a key transducer of Dectin-1 signalling. Although being dispensable for TLR/MyD88-induced responses, Card9 controls Dectin-1-mediated myeloid cell activation, cytokine production and innate anti-fungal immunity. Card9 couples to Bcl10 and regulates Bcl10–Malt1-mediated NF-κB activation induced by zymosan. Yet, Card9 is dispensable for antigen receptor signalling that uses Carma1 as a link to Bcl10–Malt1. Thus, our results define a novel innate immune pathway and indicate that evolutionarily distinct ITAM receptors in innate and adaptive immune cells use diverse adaptor proteins to engage selectively the conserved Bcl10–Malt1 module. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
29. IL-23 promotes tumour incidence and growth.
- Author
-
Langowski, John L., Xueqing Zhang, Lingling Wu, Mattson, Jeanine D., Taiying Chen, Smith, Kathy, Basham, Beth, McClanahan, Terrill, Kastelein, Robert A., and Oft, Martin
- Subjects
INFLAMMATION ,CANCER ,METALLOPROTEINASES ,IMMUNE response ,CELLULAR immunity ,T cells ,LYMPHOCYTES - Abstract
Chronic inflammation has long been associated with increased incidence of malignancy and similarities in the regulatory mechanisms have been suggested for more than a century. Infiltration of innate immune cells, elevated activities of matrix metalloproteases and increased angiogenesis and vasculature density are a few examples of the similarities between chronic and tumour-associated inflammation. Conversely, the elimination of early malignant lesions by immune surveillance, which relies on the cytotoxic activity of tumour-infiltrating T cells or intra-epithelial lymphocytes, is thought to be rate-limiting for the risk to develop cancer. Here we show a molecular connection between the rise in tumour-associated inflammation and a lack of tumour immune surveillance. Expression of the heterodimeric cytokine interleukin (IL)-23, but not of its close relative IL-12, is increased in human tumours. Expression of these cytokines antagonistically regulates local inflammatory responses in the tumour microenvironment and infiltration of intra-epithelial lymphocytes. Whereas IL-12 promotes infiltration of cytotoxic T cells, IL-23 promotes inflammatory responses such as upregulation of the matrix metalloprotease MMP9, and increases angiogenesis but reduces CD8 T-cell infiltration. Genetic deletion or antibody-mediated elimination of IL-23 leads to increased infiltration of cytotoxic T cells into the transformed tissue, rendering a protective effect against chemically induced carcinogenesis. Finally, transplanted tumours are growth-restricted in hosts depleted for IL-23 or in IL-23-receptor-deficient mice. Although many strategies for immune therapy of cancer attempt to stimulate an immune response against solid tumours, infiltration of effector cells into the tumour tissue often appears to be a critical hurdle. We show that IL-23 is an important molecular link between tumour-promoting pro-inflammatory processes and the failure of the adaptive immune surveillance to infiltrate tumours. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
30. Transforming growth factor-β induces development of the TH17 lineage.
- Author
-
Mangan, Paul R., Harrington, Laurie E., O'Quinn, Darrell B., Helms, Whitney S., Bullard, Daniel C., Elson, Charles O., Hatton, Robin D., Wahl, Sharon M., Schoeb, Trenton R., and Weaver, Casey T.
- Subjects
CELLULAR immunity ,INTERLEUKINS ,IMMUNE system ,PATHOGENIC microorganisms ,MICROORGANISMS ,GROWTH factors - Abstract
A new lineage of effector CD4
+ T cells characterized by production of interleukin (IL)-17, the T-helper-17 (TH 17) lineage, was recently described based on developmental and functional features distinct from those of classical TH 1 and TH 2 lineages. Like TH 1 and TH 2, TH 17 cells almost certainly evolved to provide adaptive immunity tailored to specific classes of pathogens, such as extracellular bacteria. Aberrant TH 17 responses have been implicated in a growing list of autoimmune disorders. TH 17 development has been linked to IL-23, an IL-12 cytokine family member that shares with IL-12 a common subunit, IL-12p40 (ref. 8). The IL-23 and IL-12 receptors also share a subunit, IL-12Rβ1, that pairs with unique, inducible components, IL-23R and IL-12Rβ2, to confer receptor responsiveness. Here we identify transforming growth factor-β (TGF-β) as a cytokine critical for commitment to TH 17 development. TGF-β acts to upregulate IL-23R expression, thereby conferring responsiveness to IL-23. Although dispensable for the development of IL-17-producing T cells in vitro and in vivo, IL-23 is required for host protection against a bacterial pathogen, Citrobacter rodentium. The action of TGF-β on naive T cells is antagonized by interferon-γ and IL-4, thus providing a mechanism for divergence of the TH 1, TH 2 and TH 17 lineages. [ABSTRACT FROM AUTHOR]- Published
- 2006
- Full Text
- View/download PDF
31. SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells.
- Author
-
Sullivan, Christopher S., Grundhoff, Adam T., Tevethia, Satvir, Pipas, James M., and Ganem, Don
- Subjects
GENE expression ,PAPILLOMAVIRUSES ,GENETIC regulation ,T cells ,MESSENGER RNA ,CELLULAR immunity - Abstract
MicroRNAs (miRNAs) are small (∼ 22-nucleotide) RNAs that in lower organisms serve important regulatory roles in development and gene expression, typically by forming imperfect duplexes with target messenger RNAs. miRNAs have also been described in mammalian cells and in infections with Epstein–Barr virus (EBV), but the function of most of them is unknown. Although one EBV miRNA probably altered the processing of a viral mRNA, the regulatory significance of this event is uncertain, because other transcripts exist that can supply the targeted function. Here we report the identification of miRNAs encoded by simian virus 40 (SV40) and define their functional significance for viral infection. SVmiRNAs accumulate at late times in infection, are perfectly complementary to early viral mRNAs, and target those mRNAs for cleavage. This reduces the expression of viral T antigens but does not reduce the yield of infectious virus relative to that generated by a mutant lacking SVmiRNAs. However, wild-type SV40-infected cells are less sensitive than the mutant to lysis by cytotoxic T cells, and trigger less cytokine production by such cells. Thus, viral evolution has taken advantage of the miRNA pathway to generate effectors that enhance the probability of successful infection. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
32. IKKalimits macrophage NF-?B activation and contributes to the resolution of inflammation.
- Author
-
Lawrence, Toby, Bebien, Magali, Liu, George Y., Nizet, Victor, and Karin, Michael
- Subjects
INFLAMMATION ,CELLULAR immunity ,TRANSCRIPTION factors ,CYTOKINES ,IMMUNOREGULATION ,CHRONIC diseases - Abstract
Inflammation and innate immunity involve signalling pathways leading to the production of inflammatory mediators. Usually such responses are self-limiting, but aberrant resolution of inflammation results in chronic diseases. Much attention has focused on pro-inflammatory signalling but little is known about the mechanisms that resolve inflammation. The I?B kinase (IKK) complex contains two catalytic subunits, IKKaand IKKß, and controls the activation of NF-?B transcription factors, which play a pivotal role in inflammation. Ample evidence indicates that IKKßmediates NF-?B activation in response to pro-inflammatory cytokines and microbial products. IKKaregulates an alternative pathway important for lymphoid organogenesis, but the role of IKKain inflammation is unknown. Here we describe a new role for IKKain the negative regulation of macrophage activation and inflammation. IKKacontributes to suppression of NF-?B activity by accelerating both the turnover of the NF-?B subunits RelA and c-Rel, and their removal from pro-inflammatory gene promoters. Inactivation of IKKain mice enhances inflammation and bacterial clearance. Hence, the two IKK catalytic subunits have evolved opposing but complimentary roles needed for the intricate control of inflammation and innate immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
33. Essential role for the p110dphosphoinositide 3-kinase in the allergic response.
- Author
-
Ali, Khaled, Bilancio, Antonio, Thomas, Matthew, Pearce, Wayne, Gilfillan, Alasdair M., Tkaczyk, Christine, Kuehn, Nicolas, Gray, Alexander, Giddings, June, Peskett, Emma, Fox, Roy, Bruce, Ian, Walker, Christoph, Sawyer, Carol, Okkenhaug, Klaus, Finan, Peter, and Vanhaesebroeck, Bart
- Subjects
MAST cells ,ALLERGIES ,ALLERGENS ,CELLULAR immunity ,CELL differentiation ,MEDICAL sciences - Abstract
Inflammatory substances released by mast cells induce and maintain the allergic response. Mast cell differentiation and activation are regulated, respectively, by stem cell factor (SCF; also known as Kit ligand) and by allergen in complex with allergen-specific immunoglobulin E (IgE). Activated SCF receptors and high-affinity receptors for IgE (Fc?RI) engage phosphoinositide 3-kinases (PI(3)Ks) to generate intracellular lipid second messenger signals. Here, we report that genetic or pharmacological inactivation of the p110disoform of PI(3)K in mast cells leads to defective SCF-mediated in vitro proliferation, adhesion and migration, and to impaired allergen-IgE-induced degranulation and cytokine release. Inactivation of p110dprotects mice against anaphylactic allergic responses. These results identify p110das a new target for therapeutic intervention in allergy and mast-cell-related pathologies. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
34. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes.
- Author
-
Janssen, Edith M., Lemmens, Edward E., Wolfe, Tom, Christen, Urs, von Herrath, Matthias G., and Schoenberger, Stephen P.
- Subjects
CD4 antigen ,T cells ,CELLULAR immunity - Abstract
A long-standing paradox in cellular immunology concerns the conditional requirement for CD4
+ T-helper (TH ) cells in the priming of cytotoxic CD8+ T lymphocyte (CTL) responses in vivo. Whereas CTL responses against certain viruses can be primed in the absence of CD4+ T cells, others, such as those mediated through ‘cross-priming’ by host antigen-presenting cells, are dependent on TH cells. A clearer understanding of the contribution of TH cells to CTL development has been hampered by the fact that most TH -independent responses have been demonstrated ex vivo as primary cytotoxic effectors, whereas TH -dependent responses generally require secondary in vitro re-stimulation for their detection. Here, we have monitored the primary and secondary responses of TH -dependent and TH -independent CTLs and find in both cases that CD4+ T cells are dispensable for primary expansion of CD8+ T cells and their differentiation into cytotoxic effectors. However, secondary CTL expansion (that is, a secondary response upon re-encounter with antigen) is wholly dependent on the presence of TH cells during, but not after, priming. Our results demonstrate that T-cell help is ‘programmed’ into CD8+ T cells during priming, conferring on these cells a hallmark of immune response memory: the capacity for functional expansion on re-encounter with antigen. [ABSTRACT FROM AUTHOR]- Published
- 2003
- Full Text
- View/download PDF
35. Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders.
- Author
-
Sánchez, Ivelisse, Mahlke, Christian, and Yuan, Junying
- Subjects
NEURODEGENERATION ,CELLULAR immunity - Abstract
The expansion of a CAG repeat coding for polyglutamine in otherwise unrelated gene products is central to eight neurodegenerative disorders including Huntington's disease. It has been well documented that expanded polyglutamine fragments, cleaved from their respective full-length proteins, form microscopically visible aggregates in affected individuals and in transgenic mice. The contribution of polyglutamine oligomers to neurodegeneration, however, is controversial. The azo-dye Congo red binds preferentially to β-sheets containing amyloid fibrils and can specifically inhibit oligomerization and disrupt preformed oligomers. Here we show that inhibition of polyglutamine oligomerization by Congo red prevents ATP depletion and caspase activation, preserves normal cellular protein synthesis and degradation functions, and promotes the clearance of expanded polyglutamine repeats in vivo and in vitro. Infusion of Congo red into a transgenic mouse model of Huntington's disease, well after the onset of symptoms, promotes the clearance of expanded repeats in vivo and exerts marked protective effects on survival, weight loss and motor function. We conclude that oligomerization is a crucial determinant in the biochemical properties of expanded polyglutamine that are central to their chronic cytotoxicity. [ABSTRACT FROM AUTHOR]
- Published
- 2003
36. Publisher Correction: Inhibition of LTβR signalling activates WNT-induced regeneration in lung
- Author
-
Dominik Pfister, Adrien Guillot, Frank Tacke, Zeynep Ertüz, Thomas M. Conlon, Meshal Ansari, Gizem Gunes, Indrabahadur Singh, Ilias Angelidis, Maja C. Funk, Darcy E. Wagner, Gerrit John-Schuster, Emmanuel Dejardin, Michael Lindner, Mareike Lehmann, Jenny Hetzer, Bernard Pirotte, Jakob Janzen, Martin Irmler, Tracy O'Connor, Lore Becker, Mathias Heikenwalder, Giorgi Beroshvili, Yan Hu, Michael Boutros, Johannes Beckers, Ali Önder Yildirim, Reinoud Gosens, Fabian J. Theis, Danijela Heide, Maximilian Strunz, Stijn E. Verleden, Melanie Königshoff, Martin Hrabé de Angelis, Gerald Burgstaller, Eric Goffin, Tobias Stoeger, Martin A. Lopez, Hani N. Alsafadi, Aicha Jeridi, Marlene Kohlhepp, Chiara Ciminieri, Percy A. Knolle, Christoph Mayr, Oliver Eickelberg, Michael Dudek, Sandra Prokosch, Herbert B. Schiller, and Rita Costa
- Subjects
Cellular immunity ,Multidisciplinary ,Signalling ,Lung ,medicine.anatomical_structure ,business.industry ,Regeneration (biology) ,medicine ,Wnt signaling pathway ,business ,Cell biology - Abstract
A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03087-6
- Published
- 2021
37. Profile: Innate ability.
- Author
-
Cyranoski, David
- Subjects
SCIENTISTS ,IMMUNE system ,IMMUNITY ,CELLULAR immunity ,LABORATORY mice ,T cells ,B cells ,DNA - Abstract
The article provides information about the immunological insight of Japanese researcher Shizuo Akira. According to the author, Akira is a man of few words and has won the honour with his prolific studies of the innate immune system. He has created an army of knock-out mice to help deduce the role of the toll-like receptors (TLR). Akira has became an independent researcher in 1996 at Hyogo College of Medicine and for decades, Akira and his team have focused their attention on acquired immunity and the domain of T-cells and B-cells that rearrange their deoxyribonucleic acid (DNA) to destroy invaders.
- Published
- 2007
- Full Text
- View/download PDF
38. Vision: New light on allergy receptor.
- Author
-
Grant, Maria
- Subjects
CELL receptors ,CELL membranes ,IMMUNE response ,CELLULAR immunity ,IMMUNOLOGY ,TREATMENT of eye diseases ,DEGENERATION (Pathology) ,NEOVASCULARIZATION ,BLOOD-vessel development ,THERAPEUTICS - Abstract
The article focuses on the implication and significance of immune cell receptor to allergy and to degenerative eye disease. Study shows that this receptor tends to be a diagnostic marker and a treatment for degenerative eye disease. It was found out that C-C Chemokine Receptor 3 (CCR3) is expressed in the endothelial cells lining the abnormal blood vessels of choroidal neovascularization (CNV) from people having wet age-related macular degeneration (AMD). It points out that CCR3 and eotaxins do not tend to contribute to the AMD pathogenesis through eosinophils recruitment.
- Published
- 2009
- Full Text
- View/download PDF
39. Mycobacterium leprae-specific protein antigens defined by cloned human helper T cells
- Author
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Diënne G. Elferink, M. Y. L. De Wit, Paul R. Klatser, Juraj Ivanyi, T. H. M. Ottenhoff, R. R. P. De Vries, and Other departments
- Subjects
Cellular immunity ,T cell ,Tuberculoid leprosy ,Lymphocyte Activation ,Epitope ,Microbiology ,Epitopes ,Antigen ,Bacterial Proteins ,medicine ,Humans ,Mycobacterium leprae ,Lepromatous leprosy ,Antigens, Bacterial ,Multidisciplinary ,biology ,Antibodies, Monoclonal ,T-Lymphocytes, Helper-Inducer ,biology.organism_classification ,medicine.disease ,Acquired immune system ,Virology ,Clone Cells ,Molecular Weight ,medicine.anatomical_structure - Abstract
Leprosy displays a remarkable spectrum of symptoms correlating with the T-cell-mediated immune reactivity of the host against the causative organism, Mycobacterium leprae. At one pole of this spectrum are lepromatous leprosy patients showing a M. leprae-specific T-cell unresponsiveness; at the other are tuberculoid leprosy patients displaying both acquired immunity and delayed-type hypersensitivity against M. leprae which are thought to be conferred by helper T (Th) cells. Because well-defined M. leprae antigens are crucial for the prevention and control of leprosy, we have cloned M. leprae-reactive T cells (TLC) of the helper phenotype from a tuberculoid leprosy patient. As reported here, these TLC show an unexpected diversity in the recognition of M. leprae and related mycobacteria, which is different from that exhibited by monoclonal antibodies. Half of these TLC are completely or almost M. leprae-specific, whereas the other half are cross-reactive with most or all other mycobacteria. A M. leprae protein of relative molecular mass (Mr) 36,000 (36K) defined by a M. leprae-specific monoclonal antibody stimulates 4 out of 6 TLC tested. Each of these TLC recognizes a different antigenic determinant, one of which is M. leprae-specific. The previous paper describes other M. leprae-specific T-cell clones half of which recognize an epitope on a M. leprae protein of Mr 18 K.
- Published
- 1986
40. The role of senescent cells in ageing
- Author
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van Deursen, Jan M.
- Subjects
Cells -- Aging ,Cellular immunity ,Cancer cells -- Physiological aspects ,Cellular signal transduction ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Cellular senescence has historically been viewed as an irreversible cell-cycle arrest mechanism that acts to protect against cancer, but recent discoveries have extended its known role to complex biological processes such as development, tissue repair, ageing and age-related disorders. New insights indicate that, unlike a static endpoint, senescence represents a series of progressive and phenotypically diverse cellular states acquired after the initial growth arrest. A deeper understanding of the molecular mechanisms underlying the multi-step progression of senescence and the development and function of acute versus chronic senescent cells may lead to new therapeutic strategies for age-related pathologies and extend healthy lifespan., Cellular senescence is a process in which cells cease dividing and undergo distinctive phenotypic alterations, including profound chromatin and secretome changes, and tumour-suppressor activation (1-6). Hayflick and Moorhead first introduced [...]
- Published
- 2014
- Full Text
- View/download PDF
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