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1.
Front Mol Neurosci ; 12: 263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787878

RESUMO

Spinal dorsal interneurons, which are generated during embryonic development, relay and process sensory inputs from the periphery to the central nervous system. Proper integration of these cells into neuronal circuitry depends on their correct positioning within the spinal parenchyma. Molecular cues that control neuronal migration have been extensively characterized but the genetic programs that regulate their production remain poorly investigated. Onecut (OC) transcription factors have been shown to control the migration of the dorsal interneurons (dINs) during spinal cord development. Here, we report that the OC factors moderate the expression of Pou2f2, a transcription factor essential for B-cell differentiation, in spinal dINs. Overexpression or inactivation of Pou2f2 leads to alterations in the differentiation of dI2, dI3 and Phox2a-positive dI5 populations and to defects in the distribution of dI2-dI6 interneurons. Thus, an OC-Pou2f2 genetic cascade regulates adequate diversification and distribution of dINs during embryonic development.

2.
Cell Mol Life Sci ; 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375869

RESUMO

Devil facial tumour disease (DFTD) comprises two genetically distinct transmissible cancers (DFT1 and DFT2) endangering the survival of the Tasmanian devil (Sarcophilus harrisii) in the wild. DFT1 first arose from a cell of the Schwann cell lineage; however, the tissue-of-origin of the recently discovered DFT2 cancer is unknown. In this study, we compared the transcriptome and proteome of DFT2 tumours to DFT1 and normal Tasmanian devil tissues to determine the tissue-of-origin of the DFT2 cancer. Our findings demonstrate that DFT2 expresses a range of Schwann cell markers and exhibits expression patterns consistent with a similar origin to the DFT1 cancer. Furthermore, DFT2 cells express genes associated with the repair response to peripheral nerve damage. These findings suggest that devils may be predisposed to transmissible cancers of Schwann cell origin. The combined effect of factors such as frequent nerve damage from biting, Schwann cell plasticity and low genetic diversity may allow these cancers to develop on rare occasions. The emergence of two independent transmissible cancers from the same tissue in the Tasmanian devil presents an unprecedented opportunity to gain insight into cancer development, evolution and immune evasion in mammalian species.

3.
Immunity ; 51(2): 337-350.e7, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31375460

RESUMO

Class-switch recombination (CSR) is a DNA recombination process that replaces the immunoglobulin (Ig) constant region for the isotype that can best protect against the pathogen. Dysregulation of CSR can cause self-reactive BCRs and B cell lymphomas; understanding the timing and location of CSR is therefore important. Although CSR commences upon T cell priming, it is generally considered a hallmark of germinal centers (GCs). Here, we have used multiple approaches to show that CSR is triggered prior to differentiation into GC B cells or plasmablasts and is greatly diminished in GCs. Despite finding a small percentage of GC B cells expressing germline transcripts, phylogenetic trees of GC BCRs from secondary lymphoid organs revealed that the vast majority of CSR events occurred prior to the onset of somatic hypermutation. As such, we have demonstrated the existence of IgM-dominated GCs, which are unlikely to occur under the assumption of ongoing switching.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Switching de Imunoglobulina , Plasmócitos/imunologia , Linfoma Plasmablástico/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Filogenia , Receptores de Antígenos de Linfócitos B/metabolismo
4.
Front Cell Neurosci ; 13: 184, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231191

RESUMO

Acquisition of proper neuronal identity and position is critical for the formation of neural circuits. In the embryonic spinal cord, cardinal populations of interneurons diversify into specialized subsets and migrate to defined locations within the spinal parenchyma. However, the factors that control interneuron diversification and migration remain poorly characterized. Here, we show that the Onecut transcription factors are necessary for proper diversification and distribution of the V2 interneurons in the developing spinal cord. Furthermore, we uncover that these proteins restrict and moderate the expression of spinal isoforms of Pou2f2, a transcription factor known to regulate B-cell differentiation. By gain- or loss-of-function experiments, we show that Pou2f2 contribute to regulate the position of V2 populations in the developing spinal cord. Thus, we uncovered a genetic pathway that regulates the diversification and the distribution of V2 interneurons during embryonic development.

5.
Immunity ; 50(1): 77-90.e5, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30611612

RESUMO

Dendritic cells (DCs) are can be broadly divided into conventional (cDC) and plasmacytoid (pDC) subsets. Despite the importance of this lineage diversity, its genetic basis is not fully understood. We found that conditional ablation of the Ets-family transcription factor PU.1 in DC-restricted progenitors led to increased pDC production at the expense of cDCs. PU.1 controlled many of the cardinal functions of DCs, such as antigen presentation by cDCs and type I interferon production by pDCs. Conditional ablation of PU.1 de-repressed the pDC transcriptional signature in cDCs. The combination of genome-wide mapping of PU.1 binding and gene expression analysis revealed a key role for PU.1 in maintaining cDC identity through the induction of the transcriptional regulator DC-SCRIPT. PU.1 activated DC-SCRIPT expression, which in turn promoted cDC formation, particularly of cDC1s, and repressed pDC development. Thus, cDC identity is regulated by a transcriptional node requiring PU.1 and DC-SCRIPT.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Células Dendríticas/fisiologia , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apresentação do Antígeno , Diferenciação Celular , Linhagem da Célula , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Células HEK293 , Humanos , Interferon Tipo I/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais , Transativadores/genética , Fatores de Transcrição/genética , Transcriptoma
6.
Nucleic Acids Res ; 47(D1): D780-D785, 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30395284

RESUMO

During haematopoiesis, haematopoietic stem cells differentiate into restricted potential progenitors before maturing into the many lineages required for oxygen transport, wound healing and immune response. We have updated Haemopedia, a database of gene-expression profiles from a broad spectrum of haematopoietic cells, to include RNA-seq gene-expression data from both mice and humans. The Haemopedia RNA-seq data set covers a wide range of lineages and progenitors, with 57 mouse blood cell types (flow sorted populations from healthy mice) and 12 human blood cell types. This data set has been made accessible for exploration and analysis, to researchers and clinicians with limited bioinformatics experience, on our online portal Haemosphere: https://www.haemosphere.org. Haemosphere also includes nine other publicly available high-quality data sets relevant to haematopoiesis. We have added the ability to compare gene expression across data sets and species by curating data sets with shared lineage designations or to view expression gene vs gene, with all plots available for download by the user.

7.
Int J Mol Sci ; 19(8)2018 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-30042348

RESUMO

Antibody Secreting Cells (ASCs) are a fundamental component of humoral immunity, however, deregulated or excessive antibody production contributes to the pathology of autoimmune diseases, while transformation of ASCs results in the malignancy Multiple Myeloma (MM). Despite substantial recent improvements in treating these conditions, there is as yet no widely used ASC-specific therapeutic approach, highlighting a critical need to identify novel methods of targeting normal and malignant ASCs. Surface molecules specifically expressed by the target cell population represent ideal candidates for a monoclonal antibody-based therapy. By interrogating the ASC gene signature that we previously defined we identified three surface proteins, Plpp5, Clptm1l and Itm2c, which represent potential targets for novel MM treatments. Plpp5, Clptm1l and Itm2c are highly and selectively expressed by mouse and human ASCs as well as MM cells. To investigate the function of these proteins within the humoral immune system we have generated three novel mouse strains, each carrying a loss-of-function mutation in either Plpp5, Clptm1l or Itm2c. Through analysis of these novel strains, we have shown that Plpp5, Clptm1l and Itm2c are dispensable for the development, maturation and differentiation of B-lymphocytes, and for the production of antibodies by ASCs. As adult mice lacking either protein showed no apparent disease phenotypes, it is likely that targeting these molecules on ASCs will have minimal on-target adverse effects.


Assuntos
Células Produtoras de Anticorpos/imunologia , Proteínas de Membrana/genética , Mieloma Múltiplo/imunologia , Proteínas de Neoplasias/genética , Fosfatidato Fosfatase/genética , Plasmócitos/imunologia , Transcriptoma , Animais , Linfócitos B/imunologia , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Linhagem Celular Tumoral , Humanos , Imunidade Humoral , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mieloma Múltiplo/genética , Mutação , Proteínas de Neoplasias/fisiologia , Fosfatidato Fosfatase/fisiologia , Plasmócitos/citologia , Cultura Primária de Células
8.
J Exp Med ; 215(8): 2073-2095, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30018075

RESUMO

Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.


Assuntos
Linfócitos B/citologia , Linfócitos B/imunologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação em Linhagem Germinativa/genética , Fosfatidilinositol 3-Quinases/genética , Animais , Afinidade de Anticorpos/imunologia , Células da Medula Óssea/citologia , Diferenciação Celular , Proliferação de Células , Criança , Mutação com Ganho de Função/genética , Humanos , Switching de Imunoglobulina , Imunoglobulinas/metabolismo , Interleucinas/farmacologia , Camundongos , Modelos Animais , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Plasmócitos/metabolismo , Transdução de Sinais
9.
Oncotarget ; 9(22): 15895-15914, 2018 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-29662615

RESUMO

As a topical cancer immunotherapy, the toll-like receptor 7 ligand imiquimod activates tumor regression via stimulation of immune cell infiltration and cytotoxic responses. Imiquimod also exerts direct pro-apoptotic effects on tumor cells in vitro, but a role for these effects in imiquimod-induced tumor regression remains undefined. We previously demonstrated that cell lines derived from devil facial tumor disease (DFTD), a transmissible cancer threatening the survival of the Tasmanian devil (Sarcophilus harrisii), are sensitive to imiquimod-induced apoptosis. In this study, the pro-apoptotic effects of imiquimod in DFTD have been investigated using RNA-sequencing and label-free quantitative proteomics. This analysis revealed that changes to gene and protein expression in imiquimod treated DFTD cells are consistent with the onset of oxidative and endoplasmic reticulum stress responses, and subsequent activation of the unfolded protein response, autophagy, cell cycle arrest and apoptosis. Imiquimod also regulates the expression of oncogenic pathways, providing a direct mechanism by which this drug may increase tumor susceptibility to immune cytotoxicity in vivo. Our study has provided the first global analysis of imiquimod-induced effects in any tumor cell line. These findings have highlighted the potential of cell stress pathways as therapeutic targets in DFTD, and will allow for improved mechanistic use of imiquimod as a therapy in both the Tasmanian devil and human cancers.

10.
Front Immunol ; 9: 259, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29515577

RESUMO

Devil facial tumor disease (DFTD) is renowned for its successful evasion of the host immune system. Down regulation of the major histocompatabilty complex class I molecule (MHC-I) on the DFTD cells is a primary mechanism of immune escape. Immunization trials on captive Tasmanian devils have previously demonstrated that an immune response against DFTD can be induced, and that immune-mediated tumor regression can occur. However, these trials were limited by their small sample sizes. Here, we describe the results of two DFTD immunization trials on cohorts of devils prior to their wild release as part of the Tasmanian Government's Wild Devil Recovery project. 95% of the devils developed anti-DFTD antibody responses. Given the relatively large sample sizes of the trials (N = 19 and N = 33), these responses are likely to reflect those of the general devil population. DFTD cells manipulated to express MHC-I were used as the antigenic basis of the immunizations in both trials. Although the adjuvant composition and number of immunizations differed between trials, similar anti-DFTD antibody levels were obtained. The first trial comprised DFTD cells and the adjuvant combination of ISCOMATRIX™, polyIC, and CpG with up to four immunizations given at monthly intervals. This compared to the second trial whereby two immunizations comprising DFTD cells and the adjuvant combination ISCOMATRIX™, polyICLC (Hiltonol®) and imiquimod were given a month apart, providing a shorter and, therefore, more practical protocol. Both trials incorporated a booster immunization given up to 5 months after the primary course. A key finding was that devils in the second trial responded more quickly and maintained their antibody levels for longer compared to devils in the first trial. The different adjuvant combination incorporating the RNAase resistant polyICLC and imiquimod used in the second trial is likely to be responsible. The seroconversion in the majority of devils in these anti-DFTD immunization trials was remarkable, especially as DFTD is hallmarked by its immune evasion mechanisms. Microsatellite analyzes of MHC revealed that some MHC-I microsatellites correlated to stronger immune responses. These trials signify the first step in the long-term objective of releasing devils with immunity to DFTD into the wild.


Assuntos
Adjuvantes Imunológicos , Vacinas Anticâncer/imunologia , Neoplasias Faciais/imunologia , Imunoterapia/métodos , Marsupiais/imunologia , Animais , Carboximetilcelulose Sódica/análogos & derivados , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Imiquimode/imunologia , Imunidade Humoral , Imunização Secundária , Imunoglobulina G/sangue , Masculino , Poli I-C/imunologia , Polilisina/análogos & derivados , Polilisina/imunologia , Evasão Tumoral
11.
Immunol Cell Biol ; 95(10): 925-932, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28875978

RESUMO

Bcl6 (B-cell lymphoma 6) is a transcriptional repressor and critical mediator of the germinal center reaction during a T-cell-dependent antibody response, where it enables somatic hypermutation of immunoglobulin genes and inhibits terminal differentiation via repression of Blimp1. It can also contribute to the development of diffuse large B-cell lymphoma when expressed inappropriately. Bcl6 regulation is mediated both at the transcriptional and post-transcriptional levels, and in particular a strong signal through the B-cell receptor causes rapid proteasomal degradation of Bcl6. Despite the importance of Bcl6 in both immunity and cancer, little is known about how other extrinsic factors regulate Bcl6 in B cells. Here we show that Bcl6 is indeed highly unstable in B cells after a B-cell receptor (BCR) signal, but that the T-cell-derived cytokines interleukin 4 (IL4) and IL21 counteract BCR-mediated degradation, preserving Bcl6 protein levels. Stat6, downstream of IL4, can induce Bcl6 transcription directly. In vivo, B-cell intrinsic loss of IL4 or IL21 signaling reduces the magnitude or duration of the GC response, respectively, while their combined loss almost completely eliminates the GC response. This work provides key insights into the effect mediated by T-follicular helper cytokines on Bcl6 regulation.


Assuntos
Linfócitos B/fisiologia , Centro Germinativo/imunologia , Interleucina-4/metabolismo , Interleucinas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Linfócitos T/imunologia , Animais , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Fator de Transcrição STAT6/genética
12.
Dev Comp Immunol ; 76: 352-360, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28689773

RESUMO

Devil facial tumour disease (DFTD) describes two genetically distinct transmissible tumours that pose a significant threat to the survival of the Tasmanian devil. A prophylactic vaccine could protect devils from DFTD transmission. For this vaccine to be effective, potent immune adjuvants will be required. Toll-like receptors (TLRs) promote robust immune responses in human cancer studies and are highly conserved across mammalian species. In this study, we investigated the proficiency of TLR ligands for immune activation in the Tasmanian devil using in vitro mononuclear cell stimulations and in vivo immunisation trials with a model antigen. We identified two such TLR ligands, polyICLC (Hiltonol®) (TLR3) and imiquimod (TLR7), that in combination induced significant IFNγ production from Tasmanian devil lymphocytes in vitro. Immunisation with these ligands and the model antigen keyhole limpet haemocyanin activated robust antigen-specific primary, secondary and long-term memory IgG responses. Our results support the conserved nature of TLR signaling across mammalian species. PolyICLC and imiquimod will be trialed as immune adjuvants in future DFTD vaccine formulations.


Assuntos
Aminoquinolinas/imunologia , Antígenos/imunologia , Vacinas Anticâncer/imunologia , Carboximetilcelulose Sódica/análogos & derivados , Neoplasias Faciais/imunologia , Leucócitos Mononucleares/imunologia , Marsupiais/imunologia , Poli I-C/imunologia , Polilisina/análogos & derivados , Adjuvantes Imunológicos , Animais , Células Cultivadas , Neoplasias Faciais/prevenção & controle , Hemocianinas/imunologia , Humanos , Imiquimode , Imunidade , Imunidade Inata , Imunização , Imunoglobulina G/metabolismo , Ativação Linfocitária , Polilisina/imunologia , Receptores Toll-Like/agonistas
13.
Sci Rep ; 7: 43827, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28276463

RESUMO

Devil facial tumour disease (DFTD) is a transmissible cancer devastating the Tasmanian devil (Sarcophilus harrisii) population. The cancer cell is the 'infectious' agent transmitted as an allograft by biting. Animals usually die within a few months with no evidence of antibody or immune cell responses against the DFTD allograft. This lack of anti-tumour immunity is attributed to an absence of cell surface major histocompatibility complex (MHC)-I molecule expression. While the endangerment of the devil population precludes experimentation on large experimental groups, those examined in our study indicated that immunisation and immunotherapy with DFTD cells expressing surface MHC-I corresponded with effective anti-tumour responses. Tumour engraftment did not occur in one of the five immunised Tasmanian devils, and regression followed therapy of experimentally induced DFTD tumours in three Tasmanian devils. Regression correlated with immune cell infiltration and antibody responses against DFTD cells. These data support the concept that immunisation of devils with DFTD cancer cells can successfully induce humoral responses against DFTD and trigger immune-mediated regression of established tumours. Our findings support the feasibility of a protective DFTD vaccine and ultimately the preservation of the species.


Assuntos
Neoplasias Faciais/imunologia , Imunização/métodos , Imunoterapia/métodos , Marsupiais/imunologia , Animais , Formação de Anticorpos/imunologia , Neoplasias Faciais/terapia , Neoplasias Faciais/veterinária , Feminino , Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Humoral/imunologia , Masculino , Resultado do Tratamento
14.
Nat Immunol ; 18(1): 96-103, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27820810

RESUMO

T lymphocytes and B lymphocytes integrate activating signals to control the size of their proliferative response. Here we report that such control was achieved by timed changes in the production rate of cell-cycle-regulating proto-oncoprotein Myc, with division cessation occurring when Myc levels fell below a critical threshold. The changing pattern of the level of Myc was not affected by cell division, which identified the regulating mechanism as a cell-intrinsic, heritable temporal controller. Overexpression of Myc in stimulated T cells and B cells did not sustain cell proliferation indefinitely, as a separate 'time-to-die' mechanism, also heritable, was programmed after lymphocyte activation and led to eventual cell loss. Together the two competing cell-intrinsic timed fates created the canonical T cell and B cell immune-response pattern of rapid growth followed by loss of most cells. Furthermore, small changes in these timed processes by regulatory signals, or by oncogenic transformation, acted in synergy to greatly enhance cell numbers over time.


Assuntos
Linfócitos B/fisiologia , Linfócitos T CD8-Positivos/fisiologia , Divisão Celular , Proliferação de Células/genética , Imunidade Celular , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Morte Celular/genética , Divisão Celular/genética , Células Cultivadas , Regulação da Expressão Gênica , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais , Transgenes/genética
15.
Front Immunol ; 7: 581, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28018348

RESUMO

The devil facial tumor disease (DFTD) is caused by clonal transmissible cancers that have led to a catastrophic decline in the wild Tasmanian devil (Sarcophilus harrisii) population. The first transmissible tumor, now termed devil facial tumor 1 (DFT1), was first discovered in 1996 and has been continually transmitted to new hosts for at least 20 years. In 2015, a second transmissible cancer [devil facial tumor 2 (DFT2)] was discovered in wild devils, and the DFT2 is genetically distinct and independent from the DFT1. Despite the estimated 136,559 base pair substitutions and 14,647 insertions/deletions in the DFT1 genome as compared to two normal devil reference genomes, the allograft tumors are not rejected by the host immune system. Additionally, genome sequencing of two sub-strains of DFT1 detected greater than 15,000 single-base substitutions that were found in only one of the DFT1 sub-strains, demonstrating the transmissible tumors are evolving and that generation of neoantigens is likely ongoing. Recent evidence in human clinical trials suggests that blocking PD-1:PD-L1 interactions promotes antitumor immune responses and is most effective in cancers with a high number of mutations. We hypothesized that DFTD cells could exploit the PD-1:PD-L1 inhibitory pathway to evade antitumor immune responses. We developed recombinant proteins and monoclonal antibodies (mAbs) to provide the first demonstration that PD-1 binds to both PD-L1 and PD-L2 in a non-placental mammal and show that PD-L1 is upregulated in DFTD cells in response to IFN-γ. Immunohistochemistry showed that PD-L1 is rarely expressed in primary tumor masses, but low numbers of PD-L1+ non-tumor cells were detected in the microenvironment of several metastatic tumors. Importantly, in vitro testing suggests that PD-1 binding to PD-L1 and PD-L2 can be blocked by mAbs, which could be critical to understanding how the DFT allografts evade the immune system.

16.
Immunity ; 45(1): 3-5, 2016 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-27438759

RESUMO

Long-lived plasma cells (LLPCs) are durable antibody-producing cells that are key to immunity. Bhattacharya and colleagues find that LLPCs derive their enhanced survival capacity from a higher rate of glucose import. Some of this glucose sustains the cells through glycolysis, while the bulk is required for antibody glycosylation.


Assuntos
Glicólise , Plasmócitos/imunologia , Anticorpos , Humanos
17.
Cancer Cell ; 30(1): 59-74, 2016 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-27374225

RESUMO

E proteins and their antagonists, the Id proteins, are transcriptional regulators important for normal hematopoiesis. We found that Id2 acts as a key regulator of leukemia stem cell (LSC) potential in MLL-rearranged acute myeloid leukemia (AML). Low endogenous Id2 expression is associated with LSC enrichment while Id2 overexpression impairs MLL-AF9-leukemia initiation and growth. Importantly, MLL-AF9 itself controls the E-protein pathway by suppressing Id2 while directly activating E2-2 expression, and E2-2 depletion phenocopies Id2 overexpression in MLL-AF9-AML cells. Remarkably, Id2 tumor-suppressive function is conserved in t(8;21) AML. Low expression of Id2 and its associated gene signature are associated with poor prognosis in MLL-rearranged and t(8;21) AML patients, identifying the Id2/E-protein axis as a promising new therapeutic target in AML.


Assuntos
Proteína 2 Inibidora de Diferenciação/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Translocação Genética , Animais , Proliferação de Células , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Regulação Leucêmica da Expressão Gênica , Humanos , Proteína 2 Inibidora de Diferenciação/metabolismo , Leucemia Mieloide Aguda/metabolismo , Camundongos , Proteína de Leucina Linfoide-Mieloide/metabolismo , Neoplasias Experimentais , Proteínas de Fusão Oncogênica/metabolismo , Prognóstico , Células-Tronco/citologia , Células-Tronco/metabolismo , Análise de Sobrevida , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo
18.
Cell Rep ; 15(4): 866-878, 2016 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-27149837

RESUMO

Plasmacytoid dendritic cells (pDCs) represent a unique immune cell type that responds to viral nucleic acids through the rapid production of type I interferons. Within the hematopoietic system, the transcription factor RUNX2 is exclusively expressed in pDCs and is required for their peripheral homeostasis. Here, we show that RUNX2 plays an essential role in promoting pDC localization and function. RUNX2 is required for the appropriate expression of the integrin-mediated adhesion machinery, as well as for the down-modulation of the chemokine receptor CXCR4, which allows pDC egress into the circulation. RUNX2 also facilitates the robust response to viral infection through the control of IRF7, the major regulator of type I interferon production. Mice lacking one copy of Runx2 have reduced numbers of peripheral pDCs and IFN-α expression, which might contribute to the reported difficulties of individuals with cleidocranial dysplasia, who are haploinsufficient for RUNX2, to clear viral infections.

19.
J Exp Med ; 213(6): 1095-111, 2016 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-27217539

RESUMO

The generation of high-affinity antibodies requires germinal center (GC) development and differentiation of long-lived plasma cells in a multilayered process that is tightly controlled by the activity of multiple transcription factors. Here, we reveal a new layer of complexity by demonstrating that dynamic changes in Id3 and E-protein activity govern both GC and plasma cell differentiation. We show that down-regulation of Id3 in B cells is essential for releasing E2A and E2-2, which in a redundant manner are required for antigen-induced B cell differentiation. We demonstrate that this pathway controls the expression of multiple key factors, including Blimp1, Xbp1, and CXCR4, and is therefore critical for establishing the transcriptional network that controls GC B cell and plasma cell differentiation.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Diferenciação Celular/imunologia , Centro Germinativo/imunologia , Proteínas Inibidoras de Diferenciação/imunologia , Plasmócitos/imunologia , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/genética , Proteínas Inibidoras de Diferenciação/genética , Camundongos , Camundongos Knockout , Fator 1 de Ligação ao Domínio I Regulador Positivo , Receptores CXCR4/genética , Receptores CXCR4/imunologia , Fator de Transcrição 4 , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/imunologia
20.
Immunol Cell Biol ; 94(7): 673-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27089941

RESUMO

Devil facial tumour disease (DFTD) is a transmissible cancer that has brought the host species, the Tasmanian devil, to the brink of extinction. The cancer cells avoid allogeneic immune recognition by downregulating cell surface major histocompatibility complex (MHC) I expression. This should prevent CD8(+) T cell, but not natural killer (NK) cell, cytotoxicity. The reason why NK cells, normally reactive to MHC-negative cells, are not activated to kill DFTD cells has not been determined. The immune response of wild devils to DFTD, if it occurs, is uncharacterised. To investigate this, we tested 12 wild devils with DFTD, and found suggestive evidence of low levels of antibodies against DFTD cells in one devil. Eight of these devils were also analysed for cytotoxicity, however, none showed evidence for cytotoxicity against cultured DFTD cells. To establish whether mimicking activation of antitumour responses could induce cytotoxic activity against DFTD, Tasmanian devil peripheral blood mononuclear cells (PBMCs) were treated with either the mitogen Concanavalin A, the Toll-like receptor agonist polyinosinic:polycytidylic acid or recombinant Tasmanian devil IL-2. All induced the PBMC cells to kill cultured DFTD cells, suggesting that activation does not occur after encounter with DFTD cells in vivo, but can be induced. The identification of agents that activate cytotoxicity against DFTD target cells is critical for developing strategies to protect against DFTD. Such agents could function as adjuvants to induce functional immune responses capable of targeting DFTD cells and tumours in vivo.


Assuntos
Neoplasias Faciais/patologia , Leucócitos Mononucleares/citologia , Marsupiais/metabolismo , Mitógenos/farmacologia , Animais , Formação de Anticorpos/efeitos dos fármacos , Formação de Anticorpos/imunologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Concanavalina A/farmacologia , Meios de Cultivo Condicionados/farmacologia , Citotoxicidade Imunológica/efeitos dos fármacos , Neoplasias Faciais/imunologia , Interleucina-2/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Poli I-C/farmacologia , Receptor 3 Toll-Like/agonistas
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