Volume 5.09 | Mar 8

Immune Regulation News 5.09 March 8, 2013
     In this issue: Publications | Reviews | Science News | Industry News | Policy News | Events | Jobs
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TOP STORY
Circuitry of Cells Involved in Immunity, Autoimmune Diseases Exposed
Scientists expand the understanding of how one type of immune cell – known as a T helper 17 or Th17 cell – develops, and how its growth influences the development of immune responses. By figuring out how these cells are “wired,” the authors make a surprising connection between autoimmunity and salt consumption, highlighting the interplay of genetics and environmental factors in disease susceptibility. [Press release from the Broad Institute discussing online prepublication in Nature] Press Release | Abstract

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PUBLICATIONS (Ranked by impact factor of the journal)

Sodium Chloride Drives Autoimmune Disease by the Induction of Pathogenic TH17 Cells
Researchers showed that increased salt (sodium chloride, NaCl) concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human interleukin-17-producing CD4+ helper T cells (TH17 cells). High-salt conditions activate the p38/MAPK pathway involving nuclear factor of activated T cells 5 and serum/glucocorticoid-regulated kinase 1 during cytokine-induced TH17 polarization. [Nature] Abstract | Press Release

Induction of Pathogenic TH17 Cells by Inducible Salt-Sensing Kinase Serum Glucocorticoid Kinase 1
Investigators used transcriptional profiling of developing interleukin-17-producing helper T cells (TH17 cells) to construct a model of their signalling network and nominate major nodes that regulate TH17 development. [Nature]
Abstract | Press Release

Autoimmune Regulator-Dependent Thymic Development of Tumor-Associated Regulatory T Cells
Researchers identified an endogenous population of antigen-specific regulatory T cells (MJ23 Tregs) found recurrently enriched in the tumors of mice with oncogene-driven prostate cancer. MJ23 Tregs were not reactive to a tumor-specific antigen but instead recognized a prostate-associated antigen that was present in tumor-free mice. [Science] Abstract

Lineage-Specific Functions of Bcl-6 in Immunity and Inflammation Are Mediated by Distinct Biochemical Mechanisms
The authors found that genetic replacement with mutated Bcl6 encoding Bcl-6 that cannot bind corepressors to its BTB domain resulted in disruption of the formation of germinal centers and affinity maturation of immunoglobulins due to a defect in the proliferation and survival of B cells. In contrast, loss of function of the BTB domain had no effect on the differentiation and function of follicular helper T cells or that of other helper T cell subsets. [Nat Immunol] Abstract | Press Release

IL-1R1 Is Required for Dendritic Cell-Mediated T Cell Reactivation within the CNS during West Nile Virus Encephalitis
Scientists found that IL-1R1 is critical for effector T cell reactivation and limits inflammation within the central nervous system (CNS) during murine West Nile virus (WNV) encephalitis. WNV-infected IL-1R1−/− mice display intact adaptive immunity in the periphery but succumb to WNV infection caused by loss of virologic control in the CNS with depressed local Th1 cytokine responses, despite parenchymal entry of virus-specific CD8+ T cells. [J Exp Med] Abstract

Class II Major Histocompatibility Complex Plays an Essential Role in Obesity-Induced Adipose Inflammation
Adipose-resident T cells (ARTs) regulate metabolic and inflammatory responses in obesity, but ART activation signals are poorly understood. Here, investigators describe class II major histocompatibility complex as an important component of high-fat-diet-induced obesity. [Cell Metab]
Abstract | Graphical Abstract | Press Release

Blockade of Individual Notch Ligands and Receptors Controls Graft-versus-Host Disease
Researchers report that γ-secretase inhibitors can block all Notch signals in alloreactive T cells, but lead to severe on-target intestinal toxicity. Using newly developed humanized antibodies and conditional genetic models, they demonstrated that Notch1/Notch2 receptors and the Notch ligands Delta-like1/4 mediate all the effects of Notch signaling in T cells during graft-versus-host disease, with dominant roles for Notch1 and Delta-like4. [J Clin Invest] Full Article | Press Release

KIR2DS1-Dependent Acquisition of CCR7 and Migratory Properties by Human NK Cells Interacting with Allogeneic HLA-C2+ DC or T Cell Blasts
The authors analyzed the role of activating KIRs in the process of CCR7 uptake by NK cells interacting with different allogeneic CCR7+ cell types. Co-incubation of freshly isolated peripheral blood NK cells or NK cell clones, expressing the HLA-C2-specific KIR2DS1 receptor, with HLA-C2+ CCR7+ lymphoblastoid cell lines resulted in increased CCR7 uptake. [Blood] Abstract

Rescue of Impaired NK Cell Activity in Hodgkin Lymphoma with Bispecific Antibodies In Vitro and in Patients
Scientists tested for functional natural killer (NK) cell defects in Hodgkin lymphoma (HL) and suggest an improvement of NK function by therapeutic means. They demonstrated that peripheral NK cells from patients with HL fail to eliminate HL cell lines in ex vivo killing assays. Impaired NK cell function correlated with elevated serum levels of soluble ligands for NK cell receptors NKp30 and NKG2D, factors known to constrict NK cell function. [Mol Ther] Abstract

Lipoxin A4 Regulates Natural Killer Cell and Type 2 Innate Lymphoid Cell Activation in Asthma
Investigators identified both natural killer (NK) cells and type 2 innate lymphoid cells (ILC2s) in human lung and peripheral blood in healthy and asthmatic subjects. Both NK cells and ILC2s expressed the pro-resolving ALX/FPR2 receptors. Lipoxin A4, a natural pro-resolving ligand for ALX/FPR2 receptors, significantly increased NK cell-mediated eosinophil apoptosis and decreased interleukin-13 release by ILC2s. [Sci Transl Med] Abstract

Regulation of Foxp3+ Inducible Regulatory T Cell Stability by SOCS2
The authors showed that despite having no effect on natural regulatory T cell (Treg) development or function, suppressor of cytokine signaling 2 (SOCS2) is highly expressed in inducible Tregs (iTregs) and required for the stable expression of Foxp3 in iTregs in vitro and in vivo. [J Immunol] Abstract

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REVIEWS
Neutrophils Usher Monocytes Into Sites of Inflammation
On sensing danger, neutrophils and monocytes adhere to the endothelium and transmigrate to the adjacent tissue via the coordinated activities of adhesion molecules, integrins, cytokines, and chemokines. Once they accumulate, these myeloid cells participate in a myriad of immune inflammatory activities. On one hand, coordinated leukocyte accumulation in injured or infected sites is required for effective pathogen elimination and tissue healing. On the other hand, uncontrolled accumulation is a defining feature of chronic diseases, such as atherosclerosis. Understanding leukocyte migration is essential to understanding the immune system. [Circ Res] Full Article
SCIENCE NEWS
Sangamo Presents New Clinical Data Demonstrating Persistent Immune System Improvements after Treatment with ZFN Therapeutic® SB-728-T
Sangamo BioSciences, Inc. announced new data from its program to develop a ‘functional cure’ for HIV/AIDS in two presentations. The first presentation described data from the SB-728-T Phase I study demonstrating that SB-728-T treatment of HIV-infected subjects leads to durable reconstitution of the immune system driven by increases in total CD4+ central memory T-cells (TCM) and CCR5-protected TCM. Data were also presented from a research stage study. [Press release from Sangamo BioSciences, Inc. discussing research presented at the 20th Conference on Retroviruses and Opportunistic Infections (CROI), Atlanta] Press Release
INDUSTRY NEWS

Takeda and Resolve Therapeutics Enter Autoimmune Partnership
Takeda Pharmaceutical Company Limited and Resolve Therapeutics, LLC jointly announced that they have entered into a partnership to develop compounds for the treatment of lupus and other autoimmune diseases. The lead compound, RSLV-132, a novel nuclease Fc fusion protein, will begin clinical development later this year. [Takeda Pharmaceutical Company Limited] Press Release

Northwest Biotherapeutics (NWBT) Provides Guidance on Phase III Trial Enrollment Timing: Completion Expected to be Faster or More Efficient than Relevant Comparison Trials

Northwest Biotherapeutics announced that it expects to complete enrollment in its 312-patient Phase III clinical trial for glioblastoma multiforme brain cancer within a period that is faster or more efficient than relevant comparison trials with immune therapies for the same brain cancer. [Northwest Biotherapeutics, Inc.] Press Release

Advanced Cell Diagnostics Initiates Agreement to Study Biomarkers for Cancer Immunotherapy
Advanced Cell Diagnostics, Inc. (ACD) announced that they have entered into an agreement with The Johns Hopkins University on behalf of its Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins to use ACD’s proprietary RNAscope® technology platform to validate novel biomarkers and drug targets for cancer immunotherapy. [Advanced Cell Diagnostics, Inc.] Press Release

POLICY NEWS

National Institutes of Health (United States)

Food and Drug Administration (United States)

Center for Biologics Evaluation and Research (United States)

European Medicines Agency (European Union)

Medicines and Healthcare Products Regulatory Agency (United Kingdom)

Therapeutic Goods Administration (Australia)

EVENTS
NEW 78th Cold Spring Harbor Symposium on Quantitative Biology: Immunity & Tolerance
May 29-June 3, 2013
Cold Spring Harbor, United States

Visit our events page to see a complete list of events in the immune regulation community.
JOB OPPORTUNITIES

Postdoctoral Fellow – Transcriptional Regulation in CD8 T Lymphocytes (Université Libre de Bruxelles – Institute for Medical Immunology)

Faculty Positions – Cancer Inflammation and Tolerance (Georgia Health Sciences University Cancer Center)

Postdoctoral Position – IL-17 and Inflammation Research (Hospices Civils de Lyon)

PhD Candidate – Immunoregulatory Properties of Stromal and Immune Cells (University of Saarland, Internal Medicine II)

Postdoctoral Position – NK/T Cells (The Ohio State University – Comprehensive Cancer Center)

Research Specialist – Tolerance and Antirejection Techniques in Transplantation (University of Chicago)

Postdoctoral Position – Immunology (Institut Pasteur)

Postdoctoral Fellow – Immunotherapeutics in Childhood Cancer (Perelman School of Medicine at the University of Pennsylvania)


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