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Cancer immunotherapies targeting the PD-1 signaling pathway

Immunotherapy has recently emerged as the fourth pillar of cancer treatment, joining surgery, radiation, and chemotherapy. While early immunotherapies focused on accelerating T-cell activity, current immune-checkpoint inhibitors take the brakes off the anti-tumor immune responses. Successful clinical trials with PD-1 monoclonal antibodies and other immune-checkpoint inhibitors have ...

Opinion: uracil DNA glycosylase (UNG) plays distinct and non-canonical roles in somatic hypermutation and class switch recombination

Activation-induced cytidine deaminase (AID) is essential to class switch recombination (CSR) and somatic hypermutation (SHM). Uracil DNA glycosylase (UNG), a member of the base excision repair complex, is required for CSR. The role of UNG in CSR and SHM is extremely controversial. AID deficiency in mice abolishes both CSR and SHM, while UNG-deficient mice have drastically reduced ...

The DSIF Subunits Spt4 and Spt5 Have Distinct Roles at Various Phases of Immunoglobulin Class Switch Recombination

Class-switch recombination (CSR), induced by activation-induced cytidine deaminase (AID), can be divided into two phases: DNA cleavage of the switch (S) regions and the joining of the cleaved ends of the different S regions. Here, we show that the DSIF complex (Spt4 and Spt5), a transcription elongation factor, is required for CSR in a switch-proficient B cell line CH12F3-2A cells, ...

In Vivo Analysis of Aicda Gene Regulation: A Critical Balance between Upstream Enhancers and Intronic Silencers Governs Appropriate Expression

The Aicda gene encodes activation-induced cytidine deaminase (AID). Aicda is strongly transcribed in activated B cells to diversify immunoglobulin genes, but expressed at low levels in various other cells in response to physiological or pathological stimuli. AID’s mutagenic nature has been shown to be involved in tumor development. Here, we used a transgenic strategy with bacterial ...

PD-1 and PD-1 ligands: from discovery to clinical application

Programmed cell death-1 (PD-1, Pdcd1), an immunoreceptor belonging to the CD28/CTLA-4 family negatively regulates antigen receptor signaling by recruiting protein tyrosine phosphatase, SHP-2 upon interacting with either of two ligands, PD-L1 or PD-L2. Because of the wide range of ligand distribution in the body, its biological significance pervades almost every aspect of immune ...

Low-affinity IgM antibodies lacking somatic hypermutations are produced in the secondary response of C57BL/6 mice to (4-hydroxy-3-nitrophenyl)acetyl hapten

Class-switched memory B cells, which are generated through the processes of somatic hypermutation (SHM) and affinity-based selection in germinal centers, contribute to the production of affinity-matured IgG antibodies in the secondary immune response. However, changes in the affinity of IgM antibodies during the immune response have not yet been studied, although IgM+ memory B ...

Cartilage-specific RBPjκ-dependent and -independent Notch signals regulate cartilage and bone development

Jackson Laboratory (Bar Harbor, ME, USA); RosaNICDf/f, Rbpjf/f and Col2CreERT2 mice were generous gifts from Drs Douglas Melton (Harvard University, MA, USA), Tasuku Honjo (Kyoto Graduate School of Medicine

Activation-Induced Cytidine Deaminase Expression in CD4+ T Cells is Associated with a Unique IL-10-Producing Subset that Increases with Age

Activation-induced cytidine deaminase (AID), produced by the Aicda gene, is essential for the immunoglobulin gene (Ig) alterations that form immune memory. Using a Cre-mediated genetic system, we unexpectedly found CD4+ T cells that had expressed Aicda (exAID cells) as well as B cells. ExAID cells increased with age, reaching up to 25% of the CD4+ and B220+ cell populations. ExAID ...

PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells

Since metastasis is the major cause of death for cancer patients, there is an urgent need to develop new therapies to control hematogenous dissemination of cancer cells. Previously we and others demonstrated a novel mechanism that allows tumors to escape from the host immune response by expressing PD-L1 which can negatively regulate immune response through the interaction with ...

PD-1 deficiency results in the development of fatal myocarditis in MRL mice

The deficiency of programmed cell death 1 (PD-1, Pdcd1), a negative immuno-receptor belonging to the CD28/cytotoxic T lymphocyte antigen 4 (CTLA-4) family, can support various tissue-specific autoimmune conditions. Here, we analyzed the effect of PD-1 deficiency in MRL mice that is genetically predisposed to systemic autoimmunity. MRL-Pdcd1−/− mice developed a fatal myocarditis, ...

Apex2 is required for efficient somatic hypermutation but not for class switch recombination of immunoglobulin genes

The DNA cleavage step in both the class switch recombination (CSR) and somatic hypermutation (SHM) of Ig genes is initiated by activation-induced cytidine deaminase (AID). However, the detailed mechanisms of the DNA strand cleavage in SHM and CSR are still largely unknown. Recently, the apurinic/apyrimidinic endonucleases, Apex1 and Apex2, were reported to be involved in the DNA ...

Identification of QTLs that modify peripheral neuropathy in NOD.H2b–Pdcd1−/− mice

The non-obese diabetic (NOD) mouse strain is prone to developing various autoimmune syndromes including type I diabetes mellitus (T1DM), sialadenitis, thyroiditis and pancreatitis. Although the genetic basis of T1DM has been extensively analyzed, genetic factors that modify the other autoimmune phenotypes are largely unknown. We have recently reported that NOD mice with ...

RBPjκ-dependent Notch signaling regulates mesenchymal progenitor cell proliferation and differentiation during skeletal development

Melton (Harvard University, MA, USA) and Dr Tasuku Honjo (Kyoto Graduate School of Medicine, Japan), respectively. Analyses of mouse embryos Embryonic tissues were harvested at E11.0-E12.5 in PBS, fixed in

Palindromic but not G-rich sequences are targets of class switch recombination

In order to understand the specificity of sequences or structures recognized by a recombinase involved in class switch recombination (CSR), we examined the relative CSR efficiency of various switch sequences in artificial CSR constructs that undergo CSR in CH12F3-2 murine B lymphoma line. Since CSR recombination is not specific to switch regions of different isotypes or orientation ...

Molecular mechanism for generation of antibody memory

Velizar Shivarov Reiko Shinkura Tomomitsu Doi Nasim A Begum Hitoshi Nagaoka Il-Mi Okazaki Satomi Ito Taichiro Nonaka Kazuo Kinoshita Tasuku Honjo Subject collections Articles on similar topics can

Roles of the ankyrin repeats and C-terminal region of the mouse Notch1 intracellular region

Hisanori Kurooka 0 Kazuki Kuroda 0 Tasuku Honjo 0 0 Department of Medical Chemistry, Kyoto University Faculty of Medicine , Yoshida, Sakyo-ku, Kyoto 606-8501, Japan The Notch intracellular region

The N- and C-terminal regions of RBP-J interact with the ankyrin repeats of Notch1 RAMIC to activate transcription

The evolutionarily-conserved DNA-binding protein RBP-J directly interacts with the RAM domain and the ankyrin (ANK) repeats of the Notch intracellular region (RAMIC), and activates transcription of downstream target genes that regulate cell differentiation. In vitro binding assays demonstrate that the truncated N- and C-terminal regions of RBP-J bind to the ANK repeats but not to ...

Evolution of class switch recombination function in fish activation-induced cytidine deaminase, AID

Following activation of mammalian B cells, class switch recombination (CSR) and somatic hypermutation (SHM) of the Ig heavy chain (IgH) gene can improve the functions of the expressed antibodies. Activation-induced cytidine deaminase (AID) is the only known B cell-specific protein required for inducing CSR and SHM in mammals. Lower vertebrates have an AID homologue, and there is ...