The BTB-ZF transcription factor Zbtb20 is driven by Irf4 to promote plasma cell differentiation and longevity
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. He...
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| Published in | The Journal of experimental medicine Vol. 211; no. 5; pp. 827 - 840 |
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| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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United States
The Rockefeller University Press
05.05.2014
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| 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. |
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| AbstractList | 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. Zbtb20 facilitates terminal differentiation of B cells into antibody-secreting cells, and its expression is dependent on Irf4 and independent of Blimp1. 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. |
| Author | Wellard, Cameron Shi, Wei Smyth, Gordon K Chevrier, Stéphane Tarlinton, David Karnowski, Alexander Chowdhury, Kamal Emslie, Dianne Corcoran, Lynn M Erikci, Erdem Kratina, Tobias |
| AuthorAffiliation | 7 CSL Limited, Bio21 Institute, Parkville, Victoria 3010, Australia 8 Department of Molecular Cell Biology, Max Planck Institute of Biophysical Chemistry, 37077 Göttingen, Germany 4 Department of Medical Biology , 5 Department of Computing and Information Systems , 6 Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria 3010, Australia 1 Molecular Immunology Division , 2 Bioinformatics Division , 3 Immunology Division, The Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia |
| AuthorAffiliation_xml | – name: 1 Molecular Immunology Division , 2 Bioinformatics Division , 3 Immunology Division, The Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia – name: 7 CSL Limited, Bio21 Institute, Parkville, Victoria 3010, Australia – name: 4 Department of Medical Biology , 5 Department of Computing and Information Systems , 6 Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria 3010, Australia – name: 8 Department of Molecular Cell Biology, Max Planck Institute of Biophysical Chemistry, 37077 Göttingen, Germany |
| Author_xml | – sequence: 1 givenname: Stéphane surname: Chevrier fullname: Chevrier, Stéphane organization: Molecular Immunology Division, 2 Bioinformatics Division, 3 Immunology Division, The Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia – sequence: 2 givenname: Dianne surname: Emslie fullname: Emslie, Dianne – sequence: 3 givenname: Wei surname: Shi fullname: Shi, Wei – sequence: 4 givenname: Tobias surname: Kratina fullname: Kratina, Tobias – sequence: 5 givenname: Cameron surname: Wellard fullname: Wellard, Cameron – sequence: 6 givenname: Alexander surname: Karnowski fullname: Karnowski, Alexander – sequence: 7 givenname: Erdem surname: Erikci fullname: Erikci, Erdem – sequence: 8 givenname: Gordon K surname: Smyth fullname: Smyth, Gordon K – sequence: 9 givenname: Kamal surname: Chowdhury fullname: Chowdhury, Kamal – sequence: 10 givenname: David surname: Tarlinton fullname: Tarlinton, David – sequence: 11 givenname: Lynn M surname: Corcoran fullname: Corcoran, Lynn M |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24711583$$D View this record in MEDLINE/PubMed |
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| Snippet | The transcriptional network regulating antibody-secreting cell (ASC) differentiation has been extensively studied, but our current understanding is limited.... Zbtb20 facilitates terminal differentiation of B cells into antibody-secreting cells, and its expression is dependent on Irf4 and independent of Blimp1. The... |
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| SubjectTerms | Animals B-Lymphocytes - metabolism Bromodeoxyuridine Cell Differentiation - physiology Cell Survival - physiology Chromatin Immunoprecipitation Enzyme-Linked Immunosorbent Assay Enzyme-Linked Immunospot Assay Flow Cytometry Gene Expression Regulation - genetics Gene Expression Regulation - physiology Immunohistochemistry Interferon Regulatory Factors - metabolism Mice Microarray Analysis Plasma Cells - physiology Real-Time Polymerase Chain Reaction Sequence Analysis, RNA Statistics, Nonparametric Transcription Factors - metabolism |
| Title | The BTB-ZF transcription factor Zbtb20 is driven by Irf4 to promote plasma cell differentiation and longevity |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/24711583 https://pubmed.ncbi.nlm.nih.gov/PMC4010913 |
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