Latest Articles Include:
- Science and gender
- Nature Immunology 11(2):99 (2010)
Gender stereotypes prevent women from attaining full recognition of their research careers. - The right team at the right time to go for a home run: tyrosine kinase activation by the TCR
- Nature Immunology 11(2):101-104 (2010)
The TCR signals via cytoplasmic tyrosine kinases. Art Weiss recounts discoveries that led to early understanding of these events. - NLRP3 has a sweet tooth
- Nature Immunology 11(2):105-106 (2010)
The signaling intermediates that activate inflammasomes are elusive. New data now show that reactive oxygen species causes TXNIP to associate with NLRP3 and activate the inflammasome. - Walking the AID tightrope
- Nature Immunology 11(2):107-109 (2010)
The mutator activation-induced cytidine deaminase is essential for immunoglobulin diversification but can be detrimental in other settings. A new comprehensive analysis investigates how its gene expression is regulated. - Taming tissue-specific T cells: CTLA-4 reins in self-reactive T cells
- Nature Immunology 11(2):109-111 (2010)
CTLA-4 is a potent coinhibitory molecule that is critical for peripheral T cell tolerance. New data suggest that CTLA-4 exerts its critical immunoregulatory functions by controlling antigen-specific conventional T cells as well as regulatory T cells. - Taming killer cells may halt diabetes progression
- Nature Immunology 11(2):111-112 (2010)
Preclinical studies in mice suggest that the natural killer cell receptor NKp46 may be a new molecular target for delaying the progression of type 1 diabetes by interfering with unexpected natural killer cell–mediated recognition of pancreatic beta cells. - Research Highlights
- Nature Immunology 11(2):113 (2010)
- Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation
- Nature Immunology 11(2):114-120 (2010)
Bcl-6 and Blimp-1 have recently been identified as key transcriptional regulators of effector and memory differentiation in CD4+ T cells and CD8+ T cells. Bcl-6 and Blimp-1 were previously known to be critical regulators of effector and memory differentiation of B lymphocytes. The new findings unexpectedly point to the Bcl-6 and Blimp-1 regulatory axis as a ubiquitous mechanism for controlling effector and memory lymphocyte differentiation and function. Bcl-6 and Blimp-1 are antagonistic transcription factors and can function as a self-reinforcing genetic switch for cell-fate decisions. However, their influences in different lymphocytes are complex. Here we review and examine the commonalities and differences in the functions of these transcription factors in CD4+ follicular helper TFH lymphocytes, effector CD8+ T lymphocytes and B lymphocytes. - The activating receptor NKp46 is essential for the development of type 1 diabetes
Gur C Porgador A Elboim M Gazit R Mizrahi S Stern-Ginossar N Achdout H Ghadially H Dor Y Nir T Doviner V Hershkovitz O Mendelson M Naparstek Y Mandelboim O - Nature Immunology 11(2):121-128 (2010)
The mechanism of action of natural killer (NK) cells in type 1 diabetes is still unknown. Here we show that the activating receptor NKp46 recognizes mouse and human ligands on pancreatic beta cells. NK cells appeared in the pancreas when insulitis progressed to type 1 diabetes, and NKp46 engagement by beta cells led to degranulation of NK cells. NKp46-deficient mice had less development of type 1 diabetes induced by injection of a low dose of streptozotocin. Injection of soluble NKp46 proteins into nonobese diabetic mice during the early phase of insulitis and the prediabetic stage prevented the development of type 1 diabetes. Our findings demonstrate that NKp46 is essential for the development of type 1 diabetes and highlight potential new therapeutic modalities for this disease. - CTLA-4 suppresses the pathogenicity of self antigen–specific T cells by cell-intrinsic and cell-extrinsic mechanisms
Ise W Kohyama M Nutsch KM Lee HM Suri A Unanue ER Murphy TL Murphy KM - Nature Immunology 11(2):129-135 (2010)
The inhibitory immunoregulatory receptor CTLA-4 is critical in maintaining self-tolerance, but the mechanisms of its actions have remained controversial. Here we examined the antigen specificity of tissue-infiltrating CD4+ T cells in Ctla4−/− mice. After adoptive transfer, T cells isolated from tissues of Ctla4−/− mice showed T cell antigen receptor (TCR)-dependent accumulation in the tissues from which they were derived, which suggested reactivity to tissue-specific antigens. We identified the pancreas-specific enzyme PDIA2 as an autoantigen in Ctla4−/− mice. CTLA-4 expressed either on PDIA2-specific effector cells or on regulatory T cells was sufficient to control tissue destruction mediated by PDIA2-specific T cells. Our results demonstrate that both cell-intrinsic and non–cell-autonomous actions of CTLA-4 operate to maintain T cell tolerance to a self antigen. - Thioredoxin-interacting protein links oxidative stress to inflammasome activation
Zhou R Tardivel A Thorens B Choi I Tschopp J - Nature Immunology 11(2):136-140 (2010)
The NLRP3 inflammasome has a major role in regulating innate immunity. Deregulated inflammasome activity is associated with several inflammatory diseases, yet little is known about the signaling pathways that lead to its activation. Here we show that NLRP3 interacted with thioredoxin (TRX)-interacting protein (TXNIP), a protein linked to insulin resistance. Inflammasome activators such as uric acid crystals induced the dissociation of TXNIP from thioredoxin in a reactive oxygen species (ROS)-sensitive manner and allowed it to bind NLRP3. TXNIP deficiency impaired activation of the NLRP3 inflammasome and subsequent secretion of interleukin 1β (IL-1β). Akin to Txnip−/− mice, Nlrp3−/− mice showed improved glucose tolerance and insulin sensitivity. The participation of TXNIP in the NLRP3 inflammasome activation may provide a mechanistic link to the observed involvement of IL-1β in the pathogenesis of type 2 diabetes. - Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21
Sheedy FJ Palsson-McDermott E Hennessy EJ Martin C O'Leary J Ruan Q Johnson DP Chen Y O'Neill LA - Nature Immunology 11(2):141-147 (2010)
The tumor suppressor PDCD4 is a proinflammatory protein that promotes activation of the transcription factor NF-κB and suppresses interleukin 10 (IL-10). Here we found that mice deficient in PDCD4 were protected from lipopolysaccharide (LPS)-induced death. The induction of NF-κB and IL-6 by LPS required PDCD4, whereas LPS enhanced IL-10 induction in cells lacking PDCD4. Treatment of human peripheral blood mononuclear cells with LPS resulted in lower PDCD4 expression, which was due to induction of the microRNA miR-21 via the adaptor MyD88 and NF-κB. Transfection of cells with a miR-21 precursor blocked NF-κB activity and promoted IL-10 production in response to LPS, whereas transfection with antisense oligonucleotides to miR-21 or targeted protection of the miR-21 site in Pdcd4 mRNA had the opposite effect. Thus, miR-21 regulates PDCD4 expression after LPS stimulation. - B cell–specific and stimulation-responsive enhancers derepress Aicda by overcoming the effects of silencers
Tran TH Nakata M Suzuki K Begum NA Shinkura R Fagarasan S Honjo T Nagaoka H - Nature Immunology 11(2):148-154 (2010)
Activation-induced cytidine deaminase (AID) is essential for the generation of antibody memory but also targets oncogenes, among other genes. We investigated the transcriptional regulation of Aicda (which encodes AID) in class switch–inducible CH12F3-2 cells and found that Aicda regulation involved derepression by several layers of positive regulatory elements in addition to the 5′ promoter region. The 5′ upstream region contained functional motifs for the response to signaling by cytokines, the ligand for the costimulatory molecule CD40 or stimuli that activated the transcription factor NF-κB. The first intron contained functional binding elements for the ubiquitous silencers c-Myb and E2f and for the B cell–specific activator Pax5 and E-box-binding proteins. Our results show that Aicda is regulated by the balance between B cell–specific and stimulation-responsive elements and ubiquitous silencers. - CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer
Stewart CR Stuart LM Wilkinson K van Gils JM Deng J Halle A Rayner KJ Boyer L Zhong R Frazier WA Lacy-Hulbert A Khoury JE Golenbock DT Moore KJ - Nature Immunology 11(2):155-161 (2010)
In atherosclerosis and Alzheimer's disease, deposition of the altered self components oxidized low-density lipoprotein (LDL) and amyloid-β triggers a protracted sterile inflammatory response. Although chronic stimulation of the innate immune system is believed to underlie the pathology of these diseases, the molecular mechanisms of activation remain unclear. Here we show that oxidized LDL and amyloid-β trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. Assembly of this newly identified heterodimer is regulated by signals from the scavenger receptor CD36, a common receptor for these disparate ligands. Our results identify CD36-TLR4-TLR6 activation as a common molecular mechanism by which atherogenic lipids and amyloid-β stimulate sterile inflammation and suggest a new model of TLR heterodimerization triggered by coreceptor signaling events. - CXCR4 acts as a costimulator during thymic β-selection
Trampont PC Tosello-Trampont AC Shen Y Duley AK Sutherland AE Bender TP Littman DR Ravichandran KS - Nature Immunology 11(2):162-170 (2010)
Passage through the β-selection developmental checkpoint requires productive rearrangement of segments of the T cell antigen receptor-β gene (Tcrb) and formation of a pre-TCR on the surface of CD4−CD8− thymocytes. How other receptors influence ββ-selection is less well understood. Here we define a new role for the chemokine receptor CXCR4 during T cell development. CXCR4 functionally associated with the pre-TCR and influenced β-selection by regulating the steady-state localization of immature thymocytes in thymic subregions, by facilitating optimal pre-TCR-induced survival signals, and by promoting thymocyte proliferation. We also characterize functionally relevant signaling molecules downstream of CXCR4 and the pre-TCR in thymocytes. Our data designate CXCR4 as a costimulator of the pre-TCR during β-selection. - Role of STAT5 in controlling cell survival and immunoglobulin gene recombination during pro-B cell development
Malin S McManus S Cobaleda C Novatchkova M Delogu A Bouillet P Strasser A Busslinger M - Nature Immunology 11(2):171-179 (2010)
STAT5 and interleukin 7 (IL-7) signaling are thought to control B lymphopoiesis by regulating the expression of key transcription factors and by activating variable (VH) gene segments at the immunoglobulin heavy-chain (Igh) locus. Using conditional mutagenesis to delete the gene encoding the transcription factor STAT5, we demonstrate that the development of pro-B cells was restored by transgenic expression of the prosurvival protein Bcl-2, which compensated for loss of the antiapoptotic protein Mcl-1. Expression of the genes encoding the B cell–specification factor EBF1 and the B cell–commitment protein Pax5 as well as VH gene recombination were normal in STAT5- or IL-7 receptor α-chain (IL-7Rα)-deficient pro-B cells rescued by Bcl-2. STAT5-expressing pro-B cells contained little or no active chromatin at most VH genes. In contrast, rearrangements of the immunoglobulin-κ light-chain locus (Igk) were more abundant in STAT5- or IL-7Rα-deficient pro-B cells. Hence! , STAT5 and IL-7 signaling control cell survival and the developmental ordering of immunoglobulin gene rearrangements by suppressing premature Igk recombination in pro-B cells.
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