Immune Regulation News Volume 8.46 | Dec 16 2016

TOP STORY

Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification

Scientists report that TCF4 comprises two transcriptional isoforms, both of which are required for optimal plasmacytoid DC (pDC) development in vitro. The long Tcf4 isoform is expressed specifically in pDCs, and its deletion in mice impaired pDCs development and led to the expansion of non-canonical CD8⁺ classical DCs. [Immunity] Abstract | Graphical Abstract

(Ranked by impact factor of the journal)

Recruitment of Calcineurin to the TCR Positively Regulates T Cell Activation

Investigators found that calcineurin was recruited to the T cell antigen receptor (TCR) signaling complex, where it reversed inhibitory phosphorylation of the tyrosine kinase Lck on Ser59 (Lck^S59). Loss of calcineurin activity impaired phosphorylation of Tyr493 of the tyrosine kinase ZAP-70, as well as some downstream pathways in a manner consistent with signaling in cells expressing Lck^S59A or Lck^S59E. [Nat Immunol] Abstract

β2-Adrenergic Receptor-Dependent Chemokine Receptor 2 Expression Regulates Leukocyte Recruitment to the Heart following Acute Injury

The authors investigated the mechanism by which immune cell-expressed β2-adrenergic receptors (β2ARs) regulate leukocyte recruitment to the heart following acute cardiac injury. Chemokine receptor 2 expression and responsiveness to C-C motif chemokine ligand 2-mediated migration were abolished in β2AR knockout bone marrow, both of which were rescued by β2AR reexpression. [Proc Natl Acad Sci USA] Abstract

Adoptive Transfer of mRNA-Transfected T Cells Redirected against Diabetogenic CD8 T Cells can Prevent Diabetes

Scientists describe mRNA electroporation for delivering peptide/β₂m/CD3-ζ genes to a reporter T-cell line and purified primary mouse CD8 T-cells. The peptide/β₂m/CD3-ζ products paired with endogenous MHC-I chains and transmitted strong activation signals upon MHC-I cross-linking. [Mol Ther] Abstract

Contraction of Intestinal Effector T Cells by Retinoic Acid-Induced Purinergic Receptor P2X7

Researchers investigated the expression mechanism and function of the purinergic receptor P2X7 in contraction of intestinal CD4⁺ effector T cells. They found that P2X7 upregulation on CD4⁺ effector T cells is induced by retinoic acid through retinoic acid receptor α binding to an intragenic enhancer region of the P2rx7 gene. [Mucosal Immunol] Abstract

MAP Kinase Phosphatase 2 Deficient Mice Develop Attenuated Experimental Autoimmune Encephalomyelitis through Regulating Dendritic Cells and T Cells

The authors investigated the mechanisms by which mitogen-activated protein kinase phosphatases (MKP-2) modulates central nervous system (CNS) inflammation in experimental autoimmune encephalomyelitis (EAE). MKP-2^−/− mice developed reduced EAE severity, associated with diminished CNS immune cell infiltration, decreased proinflammatory cytokine production and reduced frequency of CD4⁺ and CD8⁺ T cells in spleens and lymph nodes. [Sci Rep] Full Article

Differential IL-1β Secretion by Monocyte Subsets Is Regulated by Hsp27 through Modulating mRNA Stability

Scientists showed that primary human non-classical monocytes, exposed to LPS or LPS + BzATP, produce approx. 80% less IL-1β than intermediate or classical monocytes. Despite their low CD14 expression, LPS-sensing, caspase-1 activation and P2X7R activity were comparable in non-classical monocytes to other subsets: their diminished ability to produce IL-1β instead arose from 50% increased IL-1β mRNA decay rates, mediated by Hsp27. [Sci Rep] Full Article

FOXP3⁺ Regulatory T Cell Ameliorates Microvasculature in the Rejection of Mouse Orthotopic Tracheal Transplants

Scientists demonstrated that T regulatory cells (Tregs) reconstitution of allografts significantly improve tissue oxygenation, microvascular flow, epithelial repair, number of CD4⁺ CD25^highFOXP3⁺ Tregs, followed by an upregulation of proinflammatory, angiogenic and regulatory genes, while prevented subepithelial deposition of CD4⁺ T cells at d10, and collagen at d28 post-transplantation. [Clin Immunol] Abstract

The Role of Regulatory B Cell-Like Malignant Cells and T_reg Cells in the Mouse Model of BCL1 Tumor Dormancy

The authors demonstrated that the tumor site with rapidly dividing BCL1 cells has fewer regulatory T cells (Tregs) than the tumor site harboring dormant BCL1 cells. In both cases, the Tregs were equally suppressive in vitro. In spleens from mice with actively growing tumor, CD8⁺ but not CD4⁺ T cells were virtually absent. [PLoS One] Full Article

LPS-Treated Bone Marrow-Derived Dendritic Cells Induce Immune Tolerance through Modulating Differentiation of CD4⁺ Regulatory T Cell Subpopulations Mediated by 3G11 and CD127

Investigators report that there are two new subpopulations of CD4⁺CD25⁺FoxP3⁺GITR⁺ regulatory T cells. LPS-treated dendritic cells facilitate development of CD4⁺CD127⁺3G11⁻ regulatory T cells but inhibit that of CD4⁺CD127⁺3G11⁺ regulatory T cells. [Immunol Res] Abstract

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Innate Immune Signaling and Regulation in Cancer Immunotherapy

The generation of a spontaneous T cell response against tumor-associated antigens depends on innate immune activation, which drives type I interferon production. Recent work has revealed a major role for the STING pathway of cytosolic DNA sensing in this process. This cascade of events contributes to the activation of Batf3-lineage dendritic cells, which appear to be central to anti-tumor immunity. [Cell Res] Abstract

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Pioneers in Oncolytic Virus and Gene Therapy Fields Announce Formation of IGNITE Immunotherapy Inc., a Company Focused on Oncolytic Cancer Vaccine Discovery and Development

IGNITE Immunotherapy Inc. announced its formation. Along with strategic collaborative partner and lead investor Pfizer Inc., IGNITE will focus on the discovery and development of targeted and proprietary next-generation intravenous oncolytic virus vaccines for the immunotherapy of cancer. These biotherapeutics may be optimized for use in combination with immune checkpoint inhibitors. [IGNITE Immunotherapy Inc. (Business Wire, Inc.)] Press Release

Fred Hutch Opens First-of-Its Kind Bezos Family Immunotherapy Clinic

Fred Hutchinson Cancer Research Center announced the official opening of a first-of-its-kind clinic dedicated to providing immunotherapies for cancer patients in clinical trials. [Fred Hutchinson Cancer Research Center] Press Release

United Kingdom Gives Green Light for Mitochondrial Replacement Technique

Authorities in the United Kingdom have given the go-ahead for mitochondrial replacement therapy, a new type of assisted reproduction that could allow some families to avoid passing on genetic disease. The technique is controversial because it combines genetic material from three people: two eggs and one sperm. The decision has been widely anticipated. It comes after years of debate and a change in the country’s laws passed by Parliament in 2015 [Science Insider] Editorial

NIH Discusses Curbing Lab Size to Fund More Midcareer Scientists

A new analysis by the National Institutes of Health in Bethesda, Maryland, reinforces previous studies showing that productivity may lag as labs get bigger. The results suggest that NIH could fund thousands more researchers without any drop-off in scientific output if it capped the total number of grants an investigator could receive, an NIH official says. [Science Insider] Editorial

Canada’s Government Scientists Get Antimuzzling Clause in Contract

Scientists working for the Canadian government have successfully negotiated a clause in their new contract that guarantees their right to speak to the public and the media about science and their research, without needing approval from their managers. [ScienceInsider] Editorial

In Canada, Case Spurs Concern over Misconduct Secrecy

An investigation by UBC ultimately confirmed their fears: In 2014, investigators identified 29 instances of scholarly misconduct, 16 of them “serious,” including falsification and fabrication of data, according to university correspondence obtained by Retraction Watch. The tainted work had been included in 12 papers published in six journals between 2005 and 2012, investigators found, and had drawn financial support from more than a dozen government and private funders. [ScienceInsider] Editorial

Is Donald Trump Pushing More Scientists towards Political Activism?

Around the world, individual researchers and representatives of scientific societies are signing letters of protest or advice, offering to counsel Trump’s transition team and ramping up efforts to communicate the value of science to the public. [Nature News] Editorial

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