108 results on '"Corcoran LM"'
Search Results
2. Regression of devil facial tumour disease following immunotherapy in immunised Tasmanian devils
- Author
-
Tovar, C, Pye, RJ, Kreiss, A, Cheng, Y, Brown, GK, Darby, J, Malley, RC, Siddle, HVT, Skjødt, K, Kaufman, J, Silva, A, Baz Morelli, A, Papenfuss, AT, Corcoran, LM, Murphy, JM, Pearse, MJ, Belov, K, Lyons, AB, and Woods, GM
- Subjects
Male ,Marsupialia ,Treatment Outcome ,Antibody Formation ,Histocompatibility Antigens Class I ,Animals ,Female ,Immunization ,Immunotherapy ,Facial Neoplasms ,3. Good health ,Immunity, Humoral - Abstract
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.
3. Zbtb20 identifies and controls a thymus-derived population of regulatory T cells that play a role in intestinal homeostasis.
- Author
-
Krzyzanowska AK, Haynes Ii RAH, Kovalovsky D, Lin HC, Osorio L, Edelblum KL, Corcoran LM, Rabson AB, Denzin LK, and Sant'Angelo DB
- Subjects
- Animals, Homeostasis, Intestines, Mice, Mice, Knockout, Colitis chemically induced, T-Lymphocytes, Regulatory metabolism, Transcription Factors genetics
- Abstract
The expression of BTB-ZF transcription factors such as ThPOK in CD4
+ T cells, Bcl6 in T follicular helper cells, and PLZF in natural killer T cells defines the fundamental nature and characteristics of these cells. Screening for lineage-defining BTB-ZF genes led to the discovery of a subset of T cells that expressed Zbtb20. About half of Zbtb20+ T cells expressed FoxP3, the lineage-defining transcription factor for regulatory T cells (Tregs ). Zbtb20+ Tregs were phenotypically and genetically distinct from the larger conventional Treg population. Zbtb20+ Tregs constitutively expressed mRNA for interleukin-10 and produced high levels of the cytokine upon primary activation. Zbtb20+ Tregs were enriched in the intestine and specifically expanded when inflammation was induced by the use of dextran sodium sulfate. Conditional deletion of Zbtb20 in T cells resulted in a loss of intestinal epithelial barrier integrity. Consequently, knockout (KO) mice were acutely sensitive to colitis and often died because of the disease. Adoptive transfer of Zbtb20+ Tregs protected the Zbtb20 conditional KO mice from severe colitis and death, whereas non-Zbtb20 Tregs did not. Zbtb20 was detected in CD24hi double-positive and CD62Llo CD4 single-positive thymocytes, suggesting that expression of the transcription factor and the phenotype of these cells were induced during thymic development. However, Zbtb20 expression was not induced in "conventional" Tregs by activation in vitro or in vivo. Thus, Zbtb20 expression identified and controlled the function of a distinct subset of Tregs that are involved in intestinal homeostasis.- Published
- 2022
- Full Text
- View/download PDF
4. Two of a kind: transmissible Schwann cell cancers in the endangered Tasmanian devil (Sarcophilus harrisii).
- Author
-
Patchett AL, Coorens THH, Darby J, Wilson R, McKay MJ, Kamath KS, Rubin A, Wakefield M, Mcintosh L, Mangiola S, Pye RJ, Flies AS, Corcoran LM, Lyons AB, Woods GM, Murchison EP, Papenfuss AT, and Tovar C
- Subjects
- Animals, Biomarkers, Tumor genetics, Facial Neoplasms genetics, Facial Neoplasms metabolism, Facial Neoplasms pathology, Humans, Schwann Cells metabolism, Biomarkers, Tumor metabolism, Facial Neoplasms veterinary, Marsupialia physiology, Proteome analysis, Schwann Cells pathology, Transcriptome
- Abstract
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.
- Published
- 2020
- Full Text
- View/download PDF
5. Pou2f2 Regulates the Distribution of Dorsal Interneurons in the Mouse Developing Spinal Cord.
- Author
-
Masgutova G, Harris A, Jacob B, Corcoran LM, and Clotman F
- Abstract
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., (Copyright © 2019 Masgutova, Harris, Jacob, Corcoran and Clotman.)
- Published
- 2019
- Full Text
- View/download PDF
6. Class-Switch Recombination Occurs Infrequently in Germinal Centers.
- Author
-
Roco JA, Mesin L, Binder SC, Nefzger C, Gonzalez-Figueroa P, Canete PF, Ellyard J, Shen Q, Robert PA, Cappello J, Vohra H, Zhang Y, Nowosad CR, Schiepers A, Corcoran LM, Toellner KM, Polo JM, Meyer-Hermann M, Victora GD, and Vinuesa CG
- Subjects
- Animals, Cell Differentiation, Cells, Cultured, Humans, Mice, Mice, Inbred C57BL, Phylogeny, Receptors, Antigen, B-Cell metabolism, B-Lymphocytes immunology, Germinal Center immunology, Immunoglobulin Class Switching, Plasma Cells immunology, Plasmablastic Lymphoma immunology, T-Lymphocytes, Helper-Inducer immunology
- Abstract
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., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
7. Onecut Factors and Pou2f2 Regulate the Distribution of V2 Interneurons in the Mouse Developing Spinal Cord.
- Author
-
Harris A, Masgutova G, Collin A, Toch M, Hidalgo-Figueroa M, Jacob B, Corcoran LM, Francius C, and Clotman F
- Abstract
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.
- Published
- 2019
- Full Text
- View/download PDF
8. Transcription Factor PU.1 Promotes Conventional Dendritic Cell Identity and Function via Induction of Transcriptional Regulator DC-SCRIPT.
- Author
-
Chopin M, Lun AT, Zhan Y, Schreuder J, Coughlan H, D'Amico A, Mielke LA, Almeida FF, Kueh AJ, Dickins RA, Belz GT, Naik SH, Lew AM, Bouillet P, Herold MJ, Smyth GK, Corcoran LM, and Nutt SL
- Subjects
- Animals, Antigen Presentation, Cell Differentiation, Cell Lineage, DNA-Binding Proteins genetics, Gene Expression Regulation, HEK293 Cells, Humans, Interferon Type I metabolism, Mice, Mice, Transgenic, Nuclear Proteins genetics, Proto-Oncogene Proteins genetics, Signal Transduction, Trans-Activators genetics, Transcription Factors genetics, Transcriptome, DNA-Binding Proteins metabolism, Dendritic Cells physiology, Nuclear Proteins metabolism, Proto-Oncogene Proteins metabolism, Trans-Activators metabolism, Transcription Factors metabolism
- Abstract
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., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
9. Haemopedia RNA-seq: a database of gene expression during haematopoiesis in mice and humans.
- Author
-
Choi J, Baldwin TM, Wong M, Bolden JE, Fairfax KA, Lucas EC, Cole R, Biben C, Morgan C, Ramsay KA, Ng AP, Kauppi M, Corcoran LM, Shi W, Wilson N, Wilson MJ, Alexander WS, Hilton DJ, and de Graaf CA
- Subjects
- Animals, Computational Biology, Hematopoietic Stem Cells metabolism, High-Throughput Nucleotide Sequencing trends, Humans, Mice, RNA-Seq, Software, Databases, Genetic, Gene Expression genetics, Hematopoiesis genetics, Transcriptome genetics
- Abstract
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.
- Published
- 2019
- Full Text
- View/download PDF
10. Germline-activating mutations in PIK3CD compromise B cell development and function.
- Author
-
Avery DT, Kane A, Nguyen T, Lau A, Nguyen A, Lenthall H, Payne K, Shi W, Brigden H, French E, Bier J, Hermes JR, Zahra D, Sewell WA, Butt D, Elliott M, Boztug K, Meyts I, Choo S, Hsu P, Wong M, Berglund LJ, Gray P, O'Sullivan M, Cole T, Holland SM, Ma CS, Burkhart C, Corcoran LM, Phan TG, Brink R, Uzel G, Deenick EK, and Tangye SG
- Subjects
- Animals, Antibody Affinity immunology, Bone Marrow Cells cytology, Cell Differentiation, Cell Proliferation, Child, Gain of Function Mutation genetics, Humans, Immunoglobulin Class Switching, Immunoglobulins metabolism, Interleukins pharmacology, Mice, Models, Animal, Phenotype, Phosphatidylinositol 3-Kinases metabolism, Plasma Cells metabolism, Signal Transduction, B-Lymphocytes cytology, B-Lymphocytes immunology, Class I Phosphatidylinositol 3-Kinases genetics, Germ-Line Mutation genetics, Phosphatidylinositol 3-Kinases genetics
- Abstract
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., (© 2018 Avery et al.)
- Published
- 2018
- Full Text
- View/download PDF
11. Mining the Plasma Cell Transcriptome for Novel Cell Surface Proteins.
- Author
-
Trezise S, Karnowski A, Fedele PL, Mithraprabhu S, Liao Y, D'Costa K, Kueh AJ, Hardy MP, Owczarek CM, Herold MJ, Spencer A, Shi W, Willis SN, Nutt SL, and Corcoran LM
- Subjects
- Animals, B-Lymphocytes immunology, Bone Marrow Cells cytology, Bone Marrow Cells immunology, Cell Line, Tumor, Humans, Immunity, Humoral, Membrane Proteins physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Multiple Myeloma genetics, Mutation, Neoplasm Proteins physiology, Phosphatidate Phosphatase physiology, Plasma Cells cytology, Primary Cell Culture, Antibody-Producing Cells immunology, Membrane Proteins genetics, Multiple Myeloma immunology, Neoplasm Proteins genetics, Phosphatidate Phosphatase genetics, Plasma Cells immunology, Transcriptome
- Abstract
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.
- Published
- 2018
- Full Text
- View/download PDF
12. Transcriptome and proteome profiling reveals stress-induced expression signatures of imiquimod-treated Tasmanian devil facial tumor disease (DFTD) cells.
- Author
-
Patchett AL, Wilson R, Charlesworth JC, Corcoran LM, Papenfuss AT, Lyons BA, Woods GM, and Tovar C
- Abstract
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., Competing Interests: CONFLICTS OF INTEREST The authors declare no potential conflicts of interest.
- Published
- 2018
- Full Text
- View/download PDF
13. Immunization Strategies Producing a Humoral IgG Immune Response against Devil Facial Tumor Disease in the Majority of Tasmanian Devils Destined for Wild Release.
- Author
-
Pye R, Patchett A, McLennan E, Thomson R, Carver S, Fox S, Pemberton D, Kreiss A, Baz Morelli A, Silva A, Pearse MJ, Corcoran LM, Belov K, Hogg CJ, Woods GM, and Lyons AB
- Subjects
- Animals, Carboxymethylcellulose Sodium analogs & derivatives, Female, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class I metabolism, Imiquimod immunology, Immunity, Humoral, Immunization, Secondary, Immunoglobulin G blood, Male, Poly I-C immunology, Polylysine analogs & derivatives, Polylysine immunology, Tumor Escape, Adjuvants, Immunologic, Cancer Vaccines immunology, Facial Neoplasms immunology, Immunotherapy methods, Marsupialia immunology
- Abstract
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.- Published
- 2018
- Full Text
- View/download PDF
14. The toll-like receptor ligands Hiltonol ® (polyICLC) and imiquimod effectively activate antigen-specific immune responses in Tasmanian devils (Sarcophilus harrisii).
- Author
-
Patchett AL, Tovar C, Corcoran LM, Lyons AB, and Woods GM
- Subjects
- Adjuvants, Immunologic, Animals, Cells, Cultured, Facial Neoplasms prevention & control, Hemocyanins immunology, Humans, Imiquimod, Immunity, Immunity, Innate, Immunization, Immunoglobulin G metabolism, Lymphocyte Activation, Polylysine immunology, Toll-Like Receptors agonists, Aminoquinolines immunology, Antigens immunology, Cancer Vaccines immunology, Carboxymethylcellulose Sodium analogs & derivatives, Facial Neoplasms immunology, Leukocytes, Mononuclear immunology, Marsupialia immunology, Poly I-C immunology, Polylysine analogs & derivatives
- Abstract
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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
15. IL4 and IL21 cooperate to induce the high Bcl6 protein level required for germinal center formation.
- Author
-
Chevrier S, Kratina T, Emslie D, Tarlinton DM, and Corcoran LM
- Subjects
- Animals, Cells, Cultured, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Positive Regulatory Domain I-Binding Factor 1 metabolism, Proto-Oncogene Proteins c-bcl-6 genetics, Receptors, Antigen, B-Cell metabolism, STAT6 Transcription Factor genetics, B-Lymphocytes physiology, Germinal Center immunology, Interleukin-4 metabolism, Interleukins metabolism, Proto-Oncogene Proteins c-bcl-6 metabolism, T-Lymphocytes immunology
- Abstract
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.
- Published
- 2017
- Full Text
- View/download PDF
16. Regression of devil facial tumour disease following immunotherapy in immunised Tasmanian devils.
- Author
-
Tovar C, Pye RJ, Kreiss A, Cheng Y, Brown GK, Darby J, Malley RC, Siddle HV, Skjødt K, Kaufman J, Silva A, Baz Morelli A, Papenfuss AT, Corcoran LM, Murphy JM, Pearse MJ, Belov K, Lyons AB, and Woods GM
- Subjects
- Animals, Antibody Formation immunology, Facial Neoplasms therapy, Facial Neoplasms veterinary, Female, Histocompatibility Antigens Class I immunology, Immunity, Humoral immunology, Male, Treatment Outcome, Facial Neoplasms immunology, Immunization methods, Immunotherapy methods, Marsupialia immunology
- Abstract
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.
- Published
- 2017
- Full Text
- View/download PDF
17. A Myc-dependent division timer complements a cell-death timer to regulate T cell and B cell responses.
- Author
-
Heinzel S, Binh Giang T, Kan A, Marchingo JM, Lye BK, Corcoran LM, and Hodgkin PD
- Subjects
- Animals, Cell Death genetics, Cells, Cultured, Gene Expression Regulation, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-myc genetics, Signal Transduction, Transgenes genetics, B-Lymphocytes physiology, CD8-Positive T-Lymphocytes physiology, Cell Division genetics, Cell Proliferation genetics, Immunity, Cellular, Proto-Oncogene Proteins c-myc metabolism
- Abstract
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.
- Published
- 2017
- Full Text
- View/download PDF
18. PD-L1 Is Not Constitutively Expressed on Tasmanian Devil Facial Tumor Cells but Is Strongly Upregulated in Response to IFN-γ and Can Be Expressed in the Tumor Microenvironment.
- Author
-
Flies AS, Lyons AB, Corcoran LM, Papenfuss AT, Murphy JM, Knowles GW, Woods GM, and Hayball JD
- Abstract
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.- Published
- 2016
- Full Text
- View/download PDF
19. Mitogen-activated Tasmanian devil blood mononuclear cells kill devil facial tumour disease cells.
- Author
-
Brown GK, Tovar C, Cooray AA, Kreiss A, Darby J, Murphy JM, Corcoran LM, Bettiol SS, Lyons AB, and Woods GM
- Subjects
- Animals, Antibody Formation drug effects, Antibody Formation immunology, Cell Death drug effects, Cell Line, Tumor, Concanavalin A pharmacology, Culture Media, Conditioned pharmacology, Cytotoxicity, Immunologic drug effects, Facial Neoplasms immunology, Interleukin-2 pharmacology, Leukocytes, Mononuclear drug effects, Poly I-C pharmacology, Toll-Like Receptor 3 agonists, Facial Neoplasms pathology, Leukocytes, Mononuclear cytology, Marsupialia metabolism, Mitogens pharmacology
- Abstract
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.
- Published
- 2016
- Full Text
- View/download PDF
20. Long-Lived Plasma Cells Have a Sweet Tooth.
- Author
-
Corcoran LM and Nutt SL
- Subjects
- Antibodies, Humans, Glycolysis, Plasma Cells immunology
- Abstract
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., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
21. Id2 and E Proteins Orchestrate the Initiation and Maintenance of MLL-Rearranged Acute Myeloid Leukemia.
- Author
-
Ghisi M, Kats L, Masson F, Li J, Kratina T, Vidacs E, Gilan O, Doyle MA, Newbold A, Bolden JE, Fairfax KA, de Graaf CA, Firth M, Zuber J, Dickins RA, Corcoran LM, Dawson MA, Belz GT, and Johnstone RW
- Subjects
- Animals, Cell Proliferation, Chromosomes, Human, Pair 21 genetics, Chromosomes, Human, Pair 8 genetics, Gene Expression Regulation, Leukemic, Humans, Inhibitor of Differentiation Protein 2 metabolism, Leukemia, Myeloid, Acute metabolism, Mice, Myeloid-Lymphoid Leukemia Protein metabolism, Neoplasms, Experimental, Oncogene Proteins, Fusion metabolism, Prognosis, Stem Cells cytology, Stem Cells metabolism, Survival Analysis, Transcription Factor 7-Like 2 Protein metabolism, Inhibitor of Differentiation Protein 2 genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Myeloid-Lymphoid Leukemia Protein genetics, Oncogene Proteins, Fusion genetics, Transcription Factor 7-Like 2 Protein genetics, Translocation, Genetic
- Abstract
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., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
22. Characterisation of CD4 T cells in healthy and diseased koalas (Phascolarctos cinereus) using cell-type-specific monoclonal antibodies.
- Author
-
Mangar C, Armitage CW, Timms P, Corcoran LM, and Beagley KW
- Subjects
- Amino Acid Sequence, Animals, Antibodies, Monoclonal, Murine-Derived chemistry, CD4 Antigens immunology, Cell Proliferation, Cell Separation, Flow Cytometry, Hybridomas, Immunoassay, Lymph Nodes metabolism, Mice, Inbred C57BL, Phylogeny, Spleen metabolism, CD4 Antigens metabolism, CD4-Positive T-Lymphocytes immunology, Phascolarctidae immunology
- Abstract
The koala (Phascolarctos cinereus) is an arboreal herbivorous marsupial that is an Australian icon. Koalas in many parts of Australia are under multiple threats including habitat destruction, dog attacks, vehicular accidents, and infectious diseases such as Chlamydia spp. and the koala retrovirus (KoRV), which may contribute to the incidence of lymphoma and leukaemia in this species. Due to a lack of koala-specific immune reagents and assays there is currently no way to adequately analyse the immune response in healthy, diseased or vaccinated animals. This paper reports the production and characterisation of the first anti-koala CD4 monoclonal antibody (mAb). The koala CD4 gene was identified and used to develop recombinant proteins for mAb production. Fluorochrome-conjugated anti-CD4 mAb was used to measure the levels of CD4(+) lymphocytes collected from koala spleens (41.1%, range 20-45.1%) lymph nodes (36.3%, range 19-55.9%) and peripheral blood (23.8%, range 17.3-35%) by flow cytometry. Biotin-conjugated anti-CD4 mAb was used for western blot to determine an approximate size of 52 kDa for the koala CD4 molecule and used in immunohistochemistry to identify CD4(+) cells in the paracortical region and germinal centres of spleen and lymph nodes. Using the anti-CD4 mab we showed that CD4 cells from vaccinated, but not control, koalas proliferated following in vitro stimulation with UV-inactivated Chlamydia pecorum and recombinant chlamydial antigens. Since CD4(+) T cells have been shown to play a pivotal role in clearing chlamydial infection in both human and mouse infections, using this novel antibody will help determine the role CD4(+) T cells play in protection against chlamydial infection in koalas and also enhance our knowledge of how KoRV affects the koala immune system., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
23. PU.1 cooperates with IRF4 and IRF8 to suppress pre-B-cell leukemia.
- Author
-
Pang SH, Minnich M, Gangatirkar P, Zheng Z, Ebert A, Song G, Dickins RA, Corcoran LM, Mullighan CG, Busslinger M, Huntington ND, Nutt SL, and Carotta S
- Subjects
- Animals, B-Lymphocytes cytology, Gene Expression Regulation, Interferon Regulatory Factors genetics, Lymphopoiesis, Mice, Mice, Knockout, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma prevention & control, Proto-Oncogene Proteins genetics, Trans-Activators genetics, Interferon Regulatory Factors physiology, Proto-Oncogene Proteins physiology, Trans-Activators physiology
- Abstract
The Ets family transcription factor PU.1 and the interferon regulatory factor (IRF)4 and IRF8 regulate gene expression by binding to composite DNA sequences known as Ets/interferon consensus elements. Although all three factors are expressed from the onset of B-cell development, single deficiency of these factors in B-cell progenitors only mildly impacts on bone marrow B lymphopoiesis. Here we tested whether PU.1 cooperates with IRF factors in regulating early B-cell development. Lack of PU.1 and IRF4 resulted in a partial block in development the pre-B-cell stage. The combined deletion of PU.1 and IRF8 reduced recirculating B-cell numbers. Strikingly, all PU.1/IRF4 and ~50% of PU.1/IRF8 double deficient mice developed pre-B-cell acute lymphoblastic leukemia (B-ALL) associated with reduced expression of the established B-lineage tumor suppressor genes, Ikaros and Spi-B. These genes are directly regulated by PU.1/IRF4/IRF8, and restoration of Ikaros or Spi-B expression inhibited leukemic cell growth. In summary, we demonstrate that PU.1, IRF4 and IRF8 cooperate to regulate early B-cell development and to prevent pre-B-ALL formation., Competing Interests: The authors declare no competing financial interests.
- Published
- 2016
- Full Text
- View/download PDF
24. Dynamic changes in Id3 and E-protein activity orchestrate germinal center and plasma cell development.
- Author
-
Gloury R, Zotos D, Zuidscherwoude M, Masson F, Liao Y, Hasbold J, Corcoran LM, Hodgkin PD, Belz GT, Shi W, Nutt SL, Tarlinton DM, and Kallies A
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors genetics, Cell Differentiation genetics, Inhibitor of Differentiation Proteins genetics, Mice, Mice, Knockout, Positive Regulatory Domain I-Binding Factor 1, Receptors, CXCR4 genetics, Receptors, CXCR4 immunology, Transcription Factor 4, Transcription Factors genetics, Transcription Factors immunology, X-Box Binding Protein 1 genetics, X-Box Binding Protein 1 immunology, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors immunology, Basic Helix-Loop-Helix Transcription Factors immunology, Cell Differentiation immunology, Germinal Center immunology, Inhibitor of Differentiation Proteins immunology, Plasma Cells immunology
- Abstract
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., (© 2016 Gloury et al.)
- Published
- 2016
- Full Text
- View/download PDF
25. RUNX2 Mediates Plasmacytoid Dendritic Cell Egress from the Bone Marrow and Controls Viral Immunity.
- Author
-
Chopin M, Preston SP, Lun ATL, Tellier J, Smyth GK, Pellegrini M, Belz GT, Corcoran LM, Visvader JE, Wu L, and Nutt SL
- Abstract
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., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
26. NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells.
- Author
-
de Valle E, Grigoriadis G, O'Reilly LA, Willis SN, Maxwell MJ, Corcoran LM, Tsantikos E, Cornish JK, Fairfax KA, Vasanthakumar A, Febbraio MA, Hibbs ML, Pellegrini M, Banerjee A, Hodgkin PD, Kallies A, Mackay F, Strasser A, Gerondakis S, and Gugasyan R
- Subjects
- Animals, Autoimmune Diseases genetics, Autoimmune Diseases pathology, B-Lymphocytes pathology, Germinal Center pathology, Immunoglobulin M genetics, Immunoglobulin M immunology, Interleukin-6 genetics, Mice, Mice, Knockout, NF-kappa B p50 Subunit genetics, T-Lymphocytes, Helper-Inducer immunology, T-Lymphocytes, Helper-Inducer pathology, Transcription, Genetic genetics, Autoimmune Diseases immunology, B-Lymphocytes immunology, Germinal Center immunology, Interleukin-6 immunology, NF-kappa B p50 Subunit immunology, Transcription, Genetic immunology
- Abstract
We examined the role of NFκB1 in the homeostasis and function of peripheral follicular (Fo) B cells. Aging mice lacking NFκB1 (Nfκb1(-/-)) develop lymphoproliferative and multiorgan autoimmune disease attributed in large part to the deregulated activity of Nfκb1(-/-)Fo B cells that produce excessive levels of the proinflammatory cytokine interleukin 6 (IL-6). Despite enhanced germinal center (GC) B cell differentiation, the formation of GC structures was severely disrupted in the Nfκb1(-/-)mice. Bone marrow chimeric mice revealed that the Fo B cell-intrinsic loss of NFκB1 led to the spontaneous generation of GC B cells. This was primarily the result of an increase in IL-6 levels, which promotes the differentiation of Fo helper CD4(+)T cells and acts in an autocrine manner to reduce antigen receptor and toll-like receptor activation thresholds in a population of proliferating IgM(+)Nfκb1(-/-)Fo B cells. We demonstrate that p50-NFκB1 represses Il-6 transcription in Fo B cells, with the loss of NFκB1 also resulting in the uncontrolled RELA-driven transcription of Il-6.Collectively, our findings identify a previously unrecognized role for NFκB1 in preventing multiorgan autoimmunity through its negative regulation of Il-6 gene expression in Fo B cells., (© 2016 de Valle et al.)
- Published
- 2016
- Full Text
- View/download PDF
27. Regulation of germinal center responses, memory B cells and plasma cell formation-an update.
- Author
-
Corcoran LM and Tarlinton DM
- Subjects
- Animals, Antibody Formation, Humans, Immunity, Humoral, Immunologic Memory, Lymphocyte Activation physiology, B-Lymphocytes immunology, Germinal Center immunology, Plasma Cells immunology
- Abstract
Progress in understanding humoral immunity has been accelerated by the powerful experimental approaches of genetics, genomics and imaging. Excellent reviews of these advances appeared in 2015 in celebration of the 50th anniversary of the discovery of B cell and T cell lineages in the chicken. Here we provide a contemporary model of B cell differentiation, highlighting recent publications illuminating germinal center (GC), memory B cell and antibody-secreting plasma cell biology. The important contributions of CD4T cells to antibody responses have been thoroughly reviewed elsewhere., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
28. The Helix-Loop-Helix Protein ID2 Governs NK Cell Fate by Tuning Their Sensitivity to Interleukin-15.
- Author
-
Delconte RB, Shi W, Sathe P, Ushiki T, Seillet C, Minnich M, Kolesnik TB, Rankin LC, Mielke LA, Zhang JG, Busslinger M, Smyth MJ, Hutchinson DS, Nutt SL, Nicholson SE, Alexander WS, Corcoran LM, Vivier E, Belz GT, Carotta S, and Huntington ND
- Subjects
- Animals, Cell Lineage immunology, Cells, Cultured, Female, Flow Cytometry, Male, Mice, Mice, Mutant Strains, Receptors, Interleukin-15 immunology, Receptors, Interleukin-15 metabolism, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors immunology, Transcription Factors metabolism, Cell Differentiation immunology, Inhibitor of Differentiation Protein 2 immunology, Interleukin-15 immunology, Killer Cells, Natural cytology, Killer Cells, Natural immunology
- Abstract
The inhibitor of DNA binding 2 (Id2) is essential for natural killer (NK) cell development with its canonical role being to antagonize E-protein function and alternate lineage fate. Here we have identified a key role for Id2 in regulating interleukin-15 (IL-15) receptor signaling and homeostasis of NK cells by repressing multiple E-protein target genes including Socs3. Id2 deletion in mature NK cells was incompatible with their homeostasis due to impaired IL-15 receptor signaling and metabolic function and this could be rescued by strong IL-15 receptor stimulation or genetic ablation of Socs3. During NK cell maturation, we observed an inverse correlation between E-protein target genes and Id2. These results shift the current paradigm on the role of ID2, indicating that it is required not only to antagonize E-proteins during NK cell commitment, but constantly required to titrate E-protein activity to regulate NK cell fitness and responsiveness to IL-15., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
29. The flavors of plasma cells.
- Author
-
Corcoran LM and Nutt SL
- Subjects
- Animals, Cell Division genetics, Humans, B-Lymphocytes metabolism, Cell Differentiation genetics, Plasma Cells metabolism, Transcriptome
- Published
- 2015
- Full Text
- View/download PDF
30. Immunology of a Transmissible Cancer Spreading among Tasmanian Devils.
- Author
-
Woods GM, Howson LJ, Brown GK, Tovar C, Kreiss A, Corcoran LM, and Lyons AB
- Subjects
- Animals, Bites and Stings mortality, Bites and Stings pathology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes pathology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes pathology, Carnivory, Dendritic Cells immunology, Dendritic Cells pathology, Facial Neoplasms mortality, Facial Neoplasms pathology, Female, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class I immunology, Killer Cells, Natural immunology, Killer Cells, Natural pathology, Male, Mortality, Schwann Cells pathology, Tasmania, Bites and Stings immunology, Disease Transmission, Infectious, Facial Neoplasms immunology, Marsupialia immunology, Schwann Cells immunology
- Abstract
Devil facial tumor disease (DFTD) is a transmissible cancer that has killed most of the Tasmanian devil (Sarcophilus harrissii) population. Since the first case appeared in the mid-1990s, it has spread relentlessly across the Tasmanian devil's geographic range. As Tasmanian devils only exist in Tasmania, Australia, DFTD has the potential to cause extinction of this species. The origin of DFTD was a Schwann cell from a female devil. The disease is transmitted when devils bite each other around the facial areas, a behavior synonymous with this species. Every devil that is 'infected' with DFTD dies from the cancer. Once the DFTD cells have been transmitted, they appear to develop into a cancer without inducing an immune response. The DFTD cancer cells avoid allogeneic recognition because they do not express MHC class I molecules on the cell surface. A reduced genetic diversity and the production of immunosuppressive cytokines may also contribute., (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
31. Transcriptional profiling of mouse B cell terminal differentiation defines a signature for antibody-secreting plasma cells.
- Author
-
Shi W, Liao Y, Willis SN, Taubenheim N, Inouye M, Tarlinton DM, Smyth GK, Hodgkin PD, Nutt SL, and Corcoran LM
- Subjects
- Animals, B-Cell Maturation Antigen genetics, Cell Division genetics, Cell Movement genetics, Cells, Cultured, Gene Expression Profiling, Histone Code genetics, Lymphocyte Activation genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Positive Regulatory Domain I-Binding Factor 1, RNA analysis, Suppressor of Cytokine Signaling Proteins genetics, Transcription Factors genetics, Cell Differentiation genetics, Plasma Cells cytology, Plasma Cells immunology, Transcriptome
- Abstract
When B cells encounter an antigen, they alter their physiological state and anatomical localization and initiate a differentiation process that ultimately produces antibody-secreting cells (ASCs). We have defined the transcriptomes of many mature B cell populations and stages of plasma cell differentiation in mice. We provide a molecular signature of ASCs that highlights the stark transcriptional divide between B cells and plasma cells and enables the demarcation of ASCs on the basis of location and maturity. Changes in gene expression correlated with cell-division history and the acquisition of permissive histone modifications, and they included many regulators that had not been previously implicated in B cell differentiation. These findings both highlight and expand the core program that guides B cell terminal differentiation and the production of antibodies.
- Published
- 2015
- Full Text
- View/download PDF
32. The generation of antibody-secreting plasma cells.
- Author
-
Nutt SL, Hodgkin PD, Tarlinton DM, and Corcoran LM
- Subjects
- Antibody Formation immunology, Humans, Plasma Cells immunology, Antibodies immunology, B-Lymphocytes immunology, Cell Differentiation immunology, Plasma Cells metabolism
- Abstract
The regulation of antibody production is linked to the generation and maintenance of plasmablasts and plasma cells from their B cell precursors. Plasmablasts are the rapidly produced and short-lived effector cells of the early antibody response, whereas plasma cells are the long-lived mediators of lasting humoral immunity. An extraordinary number of control mechanisms, at both the cellular and molecular levels, underlie the regulation of this essential arm of the immune response. Despite this complexity, the terminal differentiation of B cells can be described as a simple probabilistic process that is governed by a central gene-regulatory network and modified by environmental stimuli.
- Published
- 2015
- Full Text
- View/download PDF
33. The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation.
- Author
-
Carotta S, Willis SN, Hasbold J, Inouye M, Pang SH, Emslie D, Light A, Chopin M, Shi W, Wang H, Morse HC 3rd, Tarlinton DM, Corcoran LM, Hodgkin PD, and Nutt SL
- Subjects
- Animals, Cell Line, Cluster Analysis, Gene Expression Profiling, Gene Expression Regulation, Humans, Immunoglobulin Class Switching genetics, Interferon Regulatory Factors metabolism, Mice, Mice, Transgenic, Plasma Cells immunology, Protein Binding, Proto-Oncogene Proteins metabolism, Trans-Activators metabolism, Cell Differentiation genetics, Interferon Regulatory Factors genetics, Plasma Cells cytology, Plasma Cells metabolism, Proto-Oncogene Proteins genetics, Trans-Activators genetics
- Abstract
Activated B cells undergo immunoglobulin class-switch recombination (CSR) and differentiate into antibody-secreting plasma cells. The distinct transcriptomes of B cells and plasma cells are maintained by the antagonistic influences of two groups of transcription factors: those that maintain the B cell program, including BCL6 and PAX5, and plasma cell-promoting factors, such as IRF4 and BLIMP-1. We show that the complex of IRF8 and PU.1 controls the propensity of B cells to undergo CSR and plasma cell differentiation by concurrently promoting the expression of BCL6 and PAX5 and repressing AID and BLIMP-1. As the PU.1-IRF8 complex functions in a reciprocal manner to IRF4, we propose that concentration-dependent competition between these factors controls B cell terminal differentiation., (© 2014 Carotta et al.)
- Published
- 2014
- Full Text
- View/download PDF
34. BTB-ZF transcription factors, a growing family of regulators of early and late B-cell development.
- Author
-
Chevrier S and Corcoran LM
- Subjects
- Animals, B-Lymphocytes cytology, Bone Marrow immunology, Hematologic Neoplasms genetics, Hematologic Neoplasms immunology, Humans, Transcription Factors genetics, Zinc Fingers genetics, B-Lymphocytes immunology, Transcription Factors immunology, Zinc Fingers immunology
- Abstract
The differentiation of early B-cell precursors in the bone marrow into the variety of mature and effector B-cell subsets of the periphery is a complex process that requires tight regulation at the transcriptional level. Different members of the broad complex, tramtrack, bric-à-brac and zinc finger (BTB-ZF) family of transcription factors have recently been shown to have key roles in many phases of B-cell development, including early B-cell development in the bone marrow, peripheral B-cell maturation and specialization into effector cells during an immune response. This review highlights the critical functions mediated by BTB-ZF transcription factors within the B-cell lineage and emphasizes how the deregulation of these transcription factors can lead to B-cell malignancies.
- Published
- 2014
- Full Text
- View/download PDF
35. The BTB-ZF transcription factor Zbtb20 is driven by Irf4 to promote plasma cell differentiation and longevity.
- Author
-
Chevrier S, Emslie D, Shi W, Kratina T, Wellard C, Karnowski A, Erikci E, Smyth GK, Chowdhury K, Tarlinton D, and Corcoran LM
- Subjects
- Animals, Bromodeoxyuridine, Chromatin Immunoprecipitation, Enzyme-Linked Immunosorbent Assay, Enzyme-Linked Immunospot Assay, Flow Cytometry, Gene Expression Regulation genetics, Immunohistochemistry, Mice, Microarray Analysis, Plasma Cells physiology, Real-Time Polymerase Chain Reaction, Sequence Analysis, RNA, Statistics, Nonparametric, B-Lymphocytes metabolism, Cell Differentiation physiology, Cell Survival physiology, Gene Expression Regulation physiology, Interferon Regulatory Factors metabolism, Transcription Factors metabolism
- Abstract
The transcriptional network regulating antibody-secreting cell (ASC) differentiation has been extensively studied, but our current understanding is limited. The mechanisms of action of known "master" regulators are still unclear, while the participation of new factors is being revealed. Here, we identify Zbtb20, a Bcl6 homologue, as a novel regulator of late B cell development. Within the B cell lineage, Zbtb20 is specifically expressed in B1 and germinal center B cells and peaks in long-lived bone marrow (BM) ASCs. Unlike Bcl6, an inhibitor of ASC differentiation, ectopic Zbtb20 expression in primary B cells facilitates terminal B cell differentiation to ASCs. In plasma cell lines, Zbtb20 induces cell survival and blocks cell cycle progression. Immunized Zbtb20-deficient mice exhibit curtailed humoral responses and accelerated loss of antigen-specific plasma cells, specifically from the BM pool. Strikingly, Zbtb20 induction does not require Blimp1 but depends directly on Irf4, acting at a newly identified Zbtb20 promoter in ASCs. These results identify Zbtb20 as an important player in late B cell differentiation and provide new insights into this complex process.
- Published
- 2014
- Full Text
- View/download PDF
36. Transcription factor IRF4 regulates germinal center cell formation through a B cell-intrinsic mechanism.
- Author
-
Willis SN, Good-Jacobson KL, Curtis J, Light A, Tellier J, Shi W, Smyth GK, Tarlinton DM, Belz GT, Corcoran LM, Kallies A, and Nutt SL
- Subjects
- Animals, Antigens immunology, B-Lymphocytes metabolism, Cell Differentiation genetics, Cell Differentiation immunology, Flow Cytometry, Gene Expression immunology, Germinal Center cytology, Germinal Center metabolism, Host-Pathogen Interactions immunology, Influenza A Virus, H3N2 Subtype immunology, Influenza A Virus, H3N2 Subtype physiology, Interferon Regulatory Factors genetics, Interferon Regulatory Factors metabolism, Leishmania major immunology, Leishmania major physiology, Leishmaniasis, Cutaneous genetics, Leishmaniasis, Cutaneous immunology, Leishmaniasis, Cutaneous microbiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Orthomyxoviridae Infections genetics, Orthomyxoviridae Infections immunology, Orthomyxoviridae Infections virology, Plasma Cells metabolism, Receptors, IgE genetics, Receptors, IgE immunology, Receptors, IgE metabolism, Sequence Analysis, RNA methods, T-Lymphocytes, Helper-Inducer metabolism, B-Lymphocytes immunology, Germinal Center immunology, Interferon Regulatory Factors immunology, Plasma Cells immunology, T-Lymphocytes, Helper-Inducer immunology
- Abstract
In response to antigenic stimulation, mature B cells interact with follicular helper T cells in specialized structures called germinal centers (GCs), which leads to the development of memory B cells and Ab-secreting plasma cells. The transcription factor IFN regulatory factor 4 (IRF4) is essential for the formation of follicular helper T cells and thus GCs, although whether IRF4 plays a distinct role in GC B cells remains contentious. RNAseq analysis on ex vivo-derived mouse B cell populations showed that Irf4 was lowly expressed in naive B cells, highly expressed in plasma cells, but absent from GC B cells. In this study, we used conditional deletion of Irf4 in mature B cells as well as wild-type and Irf4-deficient mixed bone marrow chimeric mice to investigate how and where IRF4 plays its essential role in GC formation. Strikingly, GC formation was severely impaired in mice in which Irf4 was conditionally deleted in mature B cells, after immunization with protein Ags or infection with Leishmania major. This effect was evident as early as day 5 following immunization, before the development of GCs, indicating that Irf4 was required for the development of early GC B cells. This defect was B cell intrinsic because Irf4-deficient B cells in chimeric mice failed to participate in the GC in response to L. major or influenza virus infection. Taken together, these data demonstrate a B cell-intrinsic requirement for IRF4 for not only the development of Ab secreting plasma cells but also for GC formation.
- Published
- 2014
- Full Text
- View/download PDF
37. Fas ligand-mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas.
- Author
-
Afshar-Sterle S, Zotos D, Bernard NJ, Scherger AK, Rödling L, Alsop AE, Walker J, Masson F, Belz GT, Corcoran LM, O'Reilly LA, Strasser A, Smyth MJ, Johnstone R, Tarlinton DM, Nutt SL, and Kallies A
- Subjects
- Animals, CD8-Positive T-Lymphocytes cytology, Cell Separation, Cell Transformation, Neoplastic, DNA-Binding Proteins metabolism, Disease Models, Animal, Flow Cytometry, Genes, Tumor Suppressor, Immunologic Surveillance genetics, Mice, Mice, Transgenic, Mutation, Positive Regulatory Domain I-Binding Factor 1, Proto-Oncogene Proteins c-bcl-6, Transcription Factors physiology, B-Lymphocytes pathology, Fas Ligand Protein metabolism, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse immunology, T-Lymphocytes immunology, Transcription Factors genetics
- Abstract
Loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1) or deregulated expression of the oncogene BCL6 occurs in a large proportion of diffuse large B cell lymphoma (DLBCL) cases. However, targeted mutation of either gene in mice leads to only slow and infrequent development of malignant lymphoma, and despite frequent mutation of BCL6 in activated B cells of healthy individuals, lymphoma development is rare. Here we show that T cells prevent the development of overt lymphoma in mice caused by Blimp1 deficiency or overexpression of Bcl6 in the B cell lineage. Impairment of T cell control results in rapid development of DLBCL-like disease, which can be eradicated by polyclonal CD8(+) T cells in a T cell receptor-, CD28- and Fas ligand-dependent manner. Thus, malignant transformation of mature B cells requires mutations that impair intrinsic differentiation processes and permit escape from T cell-mediated tumor surveillance.
- Published
- 2014
- Full Text
- View/download PDF
38. Germinal center-independent, IgM-mediated autoimmunity in sanroque mice lacking Obf1.
- Author
-
Chevrier S, Kratina T, Emslie D, Karnowski A, and Corcoran LM
- Subjects
- Animals, Autoantibodies immunology, B-Lymphocytes immunology, CD4-Positive T-Lymphocytes immunology, Cells, Cultured, Immunoenzyme Techniques, Mice, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Helper-Inducer immunology, Autoimmune Diseases immunology, Autoimmunity immunology, Germinal Center immunology, Glomerulonephritis immunology, Immunoglobulin G immunology, Trans-Activators physiology, Ubiquitin-Protein Ligases physiology
- Abstract
Mice homozygous for a point mutation in the Rc3h1 gene encoding Roquin1, designated sanroque mice, develop a severe antibody-mediated autoimmune condition. The disease is T-cell intrinsic, exacerbated by macrophage-intrinsic defects and driven by excessive T follicular helper cell generation and spontaneous germinal centre (GC) formation. This culminates in abnormally high numbers of plasma cells secreting high-affinity autoreactive immunoglobulin G (IgG). Obf1 is a transcriptional co-activator required for normal T-cell-dependent antibody responses, and it is essential for GC formation under all circumstances so far tested. We crossed sanroque mice with Obf1-null mice to determine whether the hyperactivity of sanroque T cells could drive Obf1(-/-) B cells to differentiate to GC B cells, or conversely, if Obf1 loss would prevent sanroque-mediated autoimmune disease. Surprisingly, while sanroque/Obf1(-/-) mice did not form GC, they still developed autoimmune disease and succumbed even more rapidly than did sanroque mice. The disease was mediated by autoreactive IgM, which may have been derived from a pre-existing population of autoreactive B cells in the Obf1(-/-) mice responding to the over-exuberant activity of sanroque CD4 cells.
- Published
- 2014
- Full Text
- View/download PDF
39. MiR-210 is induced by Oct-2, regulates B cells, and inhibits autoantibody production.
- Author
-
Mok Y, Schwierzeck V, Thomas DC, Vigorito E, Rayner TF, Jarvis LB, Prosser HM, Bradley A, Withers DR, Mårtensson IL, Corcoran LM, Blenkiron C, Miska EA, Lyons PA, and Smith KGC
- Subjects
- Animals, Autoantibodies immunology, B-Lymphocytes immunology, Cell Separation, Chromatin Immunoprecipitation, Enzyme-Linked Immunosorbent Assay, Fluorescent Antibody Technique, Mice, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs immunology, Octamer Transcription Factor-2 immunology, Oligonucleotide Array Sequence Analysis, Polymerase Chain Reaction, Transcriptome, Autoantibodies biosynthesis, B-Lymphocytes metabolism, Lymphocyte Activation immunology, MicroRNAs biosynthesis, Octamer Transcription Factor-2 metabolism
- Abstract
MicroRNAs (MiRs) are small, noncoding RNAs that regulate gene expression posttranscriptionally. In this study, we show that MiR-210 is induced by Oct-2, a key transcriptional mediator of B cell activation. Germline deletion of MiR-210 results in the development of autoantibodies from 5 mo of age. Overexpression of MiR-210 in vivo resulted in cell autonomous expansion of the B1 lineage and impaired fitness of B2 cells. Mice overexpressing MiR-210 exhibited impaired class-switched Ab responses, a finding confirmed in wild-type B cells transfected with a MiR-210 mimic. In vitro studies demonstrated defects in cellular proliferation and cell cycle entry, which were consistent with the transcriptomic analysis demonstrating downregulation of genes involved in cellular proliferation and B cell activation. These findings indicate that Oct-2 induction of MiR-210 provides a novel inhibitory mechanism for the control of B cells and autoantibody production.
- Published
- 2013
- Full Text
- View/download PDF
40. B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1.
- Author
-
Karnowski A, Chevrier S, Belz GT, Mount A, Emslie D, D'Costa K, Tarlinton DM, Kallies A, and Corcoran LM
- Subjects
- Animals, Antibodies, Viral immunology, B-Lymphocytes metabolism, Blotting, Western, Flow Cytometry, Gene Expression Regulation immunology, Germinal Center immunology, Germinal Center metabolism, Germinal Center virology, Host-Pathogen Interactions immunology, Influenza A Virus, H3N2 Subtype immunology, Influenza A Virus, H3N2 Subtype physiology, Interleukin-6 deficiency, Interleukin-6 genetics, Interleukins genetics, Interleukins metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Octamer Transcription Factor-2 genetics, Octamer Transcription Factor-2 metabolism, Orthomyxoviridae Infections genetics, Orthomyxoviridae Infections immunology, Orthomyxoviridae Infections virology, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes metabolism, T-Lymphocytes, Helper-Inducer immunology, T-Lymphocytes, Helper-Inducer metabolism, Trans-Activators genetics, Trans-Activators metabolism, B-Lymphocytes immunology, Interleukin-6 immunology, Interleukins immunology, Octamer Transcription Factor-2 immunology, T-Lymphocytes immunology, Trans-Activators immunology
- Abstract
A strong humoral response to infection requires the collaboration of several hematopoietic cell types that communicate via antigen presentation, surface coreceptors and their ligands, and secreted factors. The proinflammatory cytokine IL-6 has been shown to promote the differentiation of activated CD4(+) T cells into T follicular helper cells (T(FH) cells) during an immune response. T(FH) cells collaborate with B cells in the formation of germinal centers (GCs) during T cell-dependent antibody responses, in part through secretion of critical cytokines such as IL-21. In this study, we demonstrate that loss of either IL-6 or IL-21 has marginal effects on the generation of T(FH) cells and on the formation of GCs during the response to acute viral infection. However, mice lacking both IL-6 and IL-21 were unable to generate a robust T(FH) cell-dependent immune response. We found that IL-6 production in follicular B cells in the draining lymph node was an important early event during the antiviral response and that B cell-derived IL-6 was necessary and sufficient to induce IL-21 from CD4(+) T cells in vitro and to support T(FH) cell development in vivo. Finally, the transcriptional activator Oct2 and its cofactor OBF-1 were identified as regulators of Il6 expression in B cells.
- Published
- 2012
- Full Text
- View/download PDF
41. High rate of antibody secretion is not integral to plasma cell differentiation as revealed by XBP-1 deficiency.
- Author
-
Taubenheim N, Tarlinton DM, Crawford S, Corcoran LM, Hodgkin PD, and Nutt SL
- Subjects
- Animals, B-Lymphocyte Subsets cytology, B-Lymphocyte Subsets metabolism, Cell Differentiation genetics, Cell Proliferation, Cells, Cultured, DNA-Binding Proteins immunology, DNA-Binding Proteins metabolism, Gene Rearrangement, B-Lymphocyte immunology, Immunoglobulins genetics, Mice, Mice, Transgenic, Plasma Cells cytology, Regulatory Factor X Transcription Factors, Transcription Factors immunology, Transcription Factors metabolism, X-Box Binding Protein 1, Cell Differentiation immunology, DNA-Binding Proteins deficiency, Immunoglobulins biosynthesis, Plasma Cells immunology, Plasma Cells metabolism, Transcription Factors deficiency
- Abstract
During B cell terminal differentiation, a complex set of transcription factors interact to drive the phenotypic and functional changes leading to the development of Ab-secreting cells (ASCs). The transcription factor X-box binding protein 1 (XBP-1) is an essential part of one of the branches of the unfolded protein response (UPR). The UPR is induced when a cell has to handle large amounts of proteins, as is the case in ASCs. Although XBP-1 was initially also ascribed an indispensable function in plasma cell development, later studies of B cell-specific deletion reported a much milder consequence of XBP-1 deficiency. Our interest was to determine whether XBP-1 was integral for the differentiation of plasma cells. Using both in vitro and in vivo assays, we found efficient generation of ASCs in the absence of XBP-1. ASCs were present at normal frequencies in resting and immunized mice and displayed a pattern of surface markers typical for plasma cells. The absence of XBP-1 resulted in a reduction but not ablation of Ab secretion and the failure to develop the cellular morphology characteristic of ASCs. Thus, XBP-1 deficiency demonstrates that the gene regulatory program controlling plasma cell differentiation can proceed relatively normally in the absence of high rates of Ig secretion.
- Published
- 2012
- Full Text
- View/download PDF
42. The genetic network controlling plasma cell differentiation.
- Author
-
Nutt SL, Taubenheim N, Hasbold J, Corcoran LM, and Hodgkin PD
- Subjects
- B-Lymphocytes immunology, Humans, Models, Biological, Transcription, Genetic, B-Lymphocytes cytology, Cell Differentiation, Gene Regulatory Networks, Plasma Cells cytology
- Abstract
Upon activation by antigen, mature B cells undergo immunoglobulin class switch recombination and differentiate into antibody-secreting plasma cells, the endpoint of the B cell developmental lineage. Careful quantitation of these processes, which are stochastic, independent and strongly linked to the division history of the cell, has revealed that populations of B cells behave in a highly predictable manner. Considerable progress has also been made in the last few years in understanding the gene regulatory network that controls the B cell to plasma cell transition. The mutually exclusive transcriptomes of B cells and plasma cells are maintained by the antagonistic influences of two groups of transcription factors, those that maintain the B cell program, including Pax5, Bach2 and Bcl6, and those that promote and facilitate plasma cell differentiation, notably Irf4, Blimp1 and Xbp1. In this review, we discuss progress in the definition of both the transcriptional and cellular events occurring during late B cell differentiation, as integrating these two approaches is crucial to defining a regulatory network that faithfully reflects the stochastic features and complexity of the humoral immune response., (2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
43. Plasma cell development and survival.
- Author
-
Oracki SA, Walker JA, Hibbs ML, Corcoran LM, and Tarlinton DM
- Subjects
- Animals, B-Lymphocyte Subsets cytology, B-Lymphocyte Subsets immunology, Cell Survival, Humans, Cell Differentiation, Plasma Cells cytology, Plasma Cells immunology
- Abstract
Plasma cells have long been recognized as the basis of humoral immunity, yet we are only now beginning to appreciate the complexities of plasma cell development and the fact that not all plasma cells are created equal. In vivo, plasma cells can arise from two developmental routes: one occurring outside the follicle and another within the germinal center. A B cell's decision to follow one of these pathways is in part determined by the phenotypic subset to which it belongs and is also influenced by the nature of the antigen eliciting the response and the affinity of the B-cell receptor for that antigen. Once a plasma cell has chosen one of these pathways, the outcome of differentiation is relatively hard-wired. However, the phenotype of the plasma cells arising from these two pathways is distinct in terms of survival, location, and the quantity and quality of antibody they secrete. The extra-follicular pathway represents a relatively unchecked route to differentiation resulting in the generation of short-lived plasma cells that secrete low-affinity antibody. The germinal center response, however, allows the integration of external signals to delay plasma cell differentiation, eventually generating a plasma cell that secretes high-affinity antibody of an appropriate class, and that persists for a lifetime. The means by which these varying properties are conferred to a developing plasma cell are the subject of intense investigation.
- Published
- 2010
- Full Text
- View/download PDF
44. High-affinity B cell receptor ligation by cognate antigen induces cytokine-independent isotype switching.
- Author
-
Turner ML, Corcoran LM, Brink R, and Hodgkin PD
- Subjects
- Animals, Antibody Affinity immunology, Antigens immunology, Cell Separation, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Mice, Mice, Inbred C57BL, Muramidase immunology, Reverse Transcriptase Polymerase Chain Reaction, Antibody Formation immunology, Immunoglobulin Class Switching immunology, Lymphocyte Activation immunology, Receptors, Antigen, B-Cell immunology
- Abstract
The selection of an appropriate Ig isotype is critical for an effective immune response against pathogens. Isotype regulation is sensitive to external signals, particularly cytokines secreted by Th cells. For example, IL-4 induces isotype switching to IgG1 via a STAT6-dependent signaling pathway. In this study, we show that BCR ligation also induces IgG1 switching in mouse B cells. The extent of switch induction by Ag is affinity-dependent, and high-affinity Ag binding leads to IgG1 switching levels comparable to those induced by saturating IL-4. However, the Ag-induced IgG1 switch does not require additional cytokine signals and occurs in a STAT6-independent manner. Thus, BCR ligation represents a novel pathway for direct isotype switching leading to IgG1 secretion.
- Published
- 2010
- Full Text
- View/download PDF
45. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism.
- Author
-
Zotos D, Coquet JM, Zhang Y, Light A, D'Costa K, Kallies A, Corcoran LM, Godfrey DI, Toellner KM, Smyth MJ, Nutt SL, and Tarlinton DM
- Subjects
- Adaptive Immunity, Animals, Cell Proliferation, DNA-Binding Proteins biosynthesis, DNA-Binding Proteins immunology, Germinal Center cytology, Germinal Center immunology, Germinal Center metabolism, Interleukins metabolism, Mice, Mice, Inbred C57BL, Plasma Cells cytology, Plasma Cells immunology, Proto-Oncogene Proteins c-bcl-6, Receptors, Interleukin-21 immunology, Receptors, Interleukin-21 metabolism, T-Lymphocytes, Helper-Inducer immunology, B-Lymphocytes cytology, B-Lymphocytes immunology, Cell Differentiation immunology, Interleukins immunology, Lymphocyte Activation
- Abstract
Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are primarily a result of CD3-expressing cells producing IL-21 that acts directly on B cells. Molecularly, IL-21 maintains expression of Bcl-6 in GC B cells. The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly.
- Published
- 2010
- Full Text
- View/download PDF
46. Blimp1 is limiting for transformation in a mouse plasmacytoma model.
- Author
-
D'Costa K, Emslie D, Metcalf D, Smyth GK, Karnowski A, Kallies A, Nutt SL, and Corcoran LM
- Subjects
- Alleles, Animals, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Disease Models, Animal, Female, Genotype, Male, Mice, Mice, Transgenic, Phenotype, Plasmacytoma genetics, Plasmacytoma pathology, Positive Regulatory Domain I-Binding Factor 1, Transcription Factors genetics, Cell Transformation, Neoplastic metabolism, Plasmacytoma metabolism, Transcription Factors metabolism
- Abstract
Multiple myeloma (MM) and plasmacytomas are cancers of antibody-secreting cells (ASCs). PRDM1/BLIMP1 is an essential regulator of ASC development. Histologic evidence shows that 100% of MM expresses PRDM1/BLIMP1, indicating that PRDM1/BLIMP1 is important for the development or persistence of MM. In contrast, some diffuse large B-cell lymphomas (DLBCLs) lose PRDM1 expression, suggesting that PRDM1 may act as a tumor suppressor in DLBCL. Thus, the role of PRDM1/BLIMP1 in transformation of mature B cells is unclear. We have used a plasmacytoma-prone transgenic mouse model to study the effect of Blimp1 loss on plasmacytoma prevalence, latency, and phenotype. Two possible outcomes could be envisaged: loss of Blimp1 might decrease plasmacytoma prevalence, through reduction of plasma cells, and so the number of susceptible transformation targets. Alternatively, Blimp1 may participate in the transformation process itself. Our results support the latter scenario, showing that decreasing Blimp1 dosage does not change plasma cell number in nontransgenic mice in vivo, but it significantly reduces plasmacytoma prevalence in transgenic mice. Loss of functional Blimp1 completely prevents plasmacytoma formation in this tumor model. These observations suggest that Blimp1 is limiting for plasma cell transformation and thus has potential as a target for new therapies to combat MM.
- Published
- 2009
- Full Text
- View/download PDF
47. CD93 is required for maintenance of antibody secretion and persistence of plasma cells in the bone marrow niche.
- Author
-
Chevrier S, Genton C, Kallies A, Karnowski A, Otten LA, Malissen B, Malissen M, Botto M, Corcoran LM, Nutt SL, and Acha-Orbea H
- Subjects
- Animals, Cell Differentiation, Chickens, Ikaros Transcription Factor, Immunization, Mammary Tumor Virus, Mouse immunology, Mice, Plasma Cells cytology, Positive Regulatory Domain I-Binding Factor 1, Retroviridae Infections immunology, Syndecan-1 immunology, T-Lymphocytes immunology, Trans-Activators immunology, Transcription Factors immunology, gamma-Globulins immunology, Antibody Formation immunology, Bone Marrow immunology, Membrane Glycoproteins immunology, Plasma Cells immunology, Receptors, Complement immunology
- Abstract
Plasma cells represent the end stage of B-cell development and play a key role in providing an efficient antibody response, but they are also involved in numerous pathologies. Here we show that CD93, a receptor expressed during early B-cell development, is reinduced during plasma-cell differentiation. High CD93/CD138 expression was restricted to antibody-secreting cells both in T-dependent and T-independent responses as naive, memory, and germinal-center B cells remained CD93-negative. CD93 was expressed on (pre)plasmablasts/plasma cells, including long-lived plasma cells that showed decreased cell cycle activity, high levels of isotype-switched Ig secretion, and modification of the transcriptional network. T-independent and T-dependent stimuli led to re-expression of CD93 via 2 pathways, either before or after CD138 or Blimp-1 expression. Strikingly, while humoral immune responses initially proceeded normally, CD93-deficient mice were unable to maintain antibody secretion and bone-marrow plasma-cell numbers, demonstrating that CD93 is important for the maintenance of plasma cells in bone marrow niches.
- Published
- 2009
- Full Text
- View/download PDF
48. Oct2 enhances antibody-secreting cell differentiation through regulation of IL-5 receptor alpha chain expression on activated B cells.
- Author
-
Emslie D, D'Costa K, Hasbold J, Metcalf D, Takatsu K, Hodgkin PO, and Corcoran LM
- Subjects
- Animals, Antibody-Producing Cells drug effects, Antibody-Producing Cells immunology, B-Lymphocytes cytology, B-Lymphocytes drug effects, Cell Differentiation drug effects, Cell Differentiation immunology, Cell Line, Eosinophils drug effects, Eosinophils immunology, Gene Expression Regulation drug effects, Interleukin-5 pharmacology, Interleukin-5 Receptor alpha Subunit genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Octamer Transcription Factor-2 deficiency, Octamer Transcription Factor-2 genetics, Positive Regulatory Domain I-Binding Factor 1, RNA, Messenger metabolism, Repressor Proteins genetics, Repressor Proteins immunology, Spleen cytology, T-Lymphocytes drug effects, T-Lymphocytes immunology, Transcription Factors genetics, Transcription Factors immunology, Antibody-Producing Cells cytology, B-Lymphocytes immunology, Interleukin-5 Receptor alpha Subunit immunology, Octamer Transcription Factor-2 immunology
- Abstract
Mice lacking a functional gene for the Oct2 transcriptional activator display several developmental and functional deficiencies in the B lymphocyte lineage. These include defective B cell receptor (BCR) and Toll-like receptor 4 signaling, an absence of B-1 and marginal zone populations, and globally reduced levels of serum immunoglobulin (Ig) in naive and immunized animals. Oct2 was originally identified through its ability to bind to regulatory regions in the Ig loci, but genetic evidence has not supported an essential role for Oct2 in the expression of Ig genes. We describe a new Oct2-mediated role in B cells. Oct2 augments the ability of activated B cells to differentiate to antibody-secreting plasma cells (ASCs) under T cell-dependent conditions through direct regulation of the gene encoding the alpha chain of the interleukin (IL) 5 receptor. Ectopic expression of IL-5Ralpha in oct2-deficient B cells largely restores their ability to differentiate to functional ASCs in vitro but does not correct other phenotypic defects in the mutants, such as the maturation and specialization of peripheral B cells, which must therefore rely on distinct Oct2 target genes. IL-5 augments ASC differentiation in vitro, and we show that IL-5 directly activates the plasma cell differentiation program by enhancing blimp1 expression.
- Published
- 2008
- Full Text
- View/download PDF
49. Identification of Pax5 target genes in early B cell differentiation.
- Author
-
Pridans C, Holmes ML, Polli M, Wettenhall JM, Dakic A, Corcoran LM, Smyth GK, and Nutt SL
- Subjects
- Animals, Cell Differentiation genetics, Gene Expression Profiling, Mice, Mice, Mutant Strains, Oligonucleotide Array Sequence Analysis, PAX5 Transcription Factor genetics, Transcription Factors genetics, B-Lymphocytes immunology, Cell Lineage genetics, Gene Expression Regulation, Developmental, Lymphocyte Activation genetics, PAX5 Transcription Factor physiology
- Abstract
The transcription factor Pax5 is essential for B cell commitment in the mouse, where it represses lineage-inappropriate gene expression while simultaneously activating the B cell gene expression program. In this study we have performed a global gene expression screen of wild-type and Pax5-deficient pro-B cells in an attempt to identify the crucial Pax5 targets in early B lymphopoiesis. These studies have identified 109 Pax5 targets comprising 61% activated and 39% repressed genes. Interestingly, Pax5 directly regulates the genes encoding a number of transcription factors that are required at the pre-B cell stage of differentiation, including Irf8, Spib, and Ikzf3 (Aiolos), suggesting that a key function of Pax5 is to activate secondary transcription factors that further reinforce the B cell program. Pax5 is also required for the expression of many genes known to be involved in adhesion and signaling, indicating that Pax5 modulates the homing and or migration properties of B cell progenitors. Finally, Pax5 also represses a cohort of genes that are involved in multiple biological processes, many of which are not typically associated with B cells. These include the repression of the adhesion molecule Embigin, which is expressed in bone marrow progenitors, T cells, and myeloid cells but is specifically repressed by Pax5 in B cells.
- Published
- 2008
- Full Text
- View/download PDF
50. Silencing and nuclear repositioning of the lambda5 gene locus at the pre-B cell stage requires Aiolos and OBF-1.
- Author
-
Karnowski A, Cao C, Matthias G, Carotta S, Corcoran LM, Martensson IL, Skok JA, and Matthias P
- Subjects
- Animals, Bone Marrow Cells metabolism, Bone Marrow Cells physiology, Cell Differentiation genetics, Cell Differentiation immunology, Cell Nucleus genetics, Cells, Cultured, Gene Expression Profiling, Gene Expression Regulation immunology, Ikaros Transcription Factor, Immunoglobulin lambda-Chains metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Precursor Cells, B-Lymphoid physiology, Trans-Activators genetics, Gene Order physiology, Gene Rearrangement, B-Lymphocyte, Light Chain, Gene Silencing immunology, Immunoglobulin lambda-Chains genetics, Precursor Cells, B-Lymphoid metabolism, Trans-Activators physiology
- Abstract
The chromatin regulator Aiolos and the transcriptional coactivator OBF-1 have been implicated in regulating aspects of B cell maturation and activation. Mice lacking either of these factors have a largely normal early B cell development. However, when both factors are eliminated simultaneously a block is uncovered at the transition between pre-B and immature B cells, indicating that these proteins exert a critical function in developing B lymphocytes. In mice deficient for Aiolos and OBF-1, the numbers of immature B cells are reduced, small pre-BII cells are increased and a significant impairment in immunoglobulin light chain DNA rearrangement is observed. We identified genes whose expression is deregulated in the pre-B cell compartment of these mice. In particular, we found that components of the pre-BCR, such as the surrogate light chain genes lambda5 and VpreB, fail to be efficiently silenced in double-mutant mice. Strikingly, developmentally regulated nuclear repositioning of the lambda5 gene is impaired in pre-B cells lacking OBF-1 and Aiolos. These studies uncover a novel role for OBF-1 and Aiolos in controlling the transcription and nuclear organization of genes involved in pre-BCR function.
- Published
- 2008
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.