During affinity maturation, germinal center (GC) B cells alternate between proliferation and somatic hypermutation in the dark zone (DZ) and affinity-dependent selection in the light zone (LZ). This anatomical segregation imposes that the vigorous proliferation that allows clonal expansion of positively selected GC B cells takes place ostensibly in the absence of the signals that triggered selection in the LZ, as if by “inertia.” We find that such inertial cycles specifically require the cell cycle regulator cyclin D3. Cyclin D3 dose-dependently controls the extent to which B cells proliferate in the DZ and is essential for effective clonal expansion of GC B cells in response to strong T follicular helper (Tfh) cell help. Introduction into the Ccnd3 gene of a Burkitt lymphoma–associated gain-of-function mutation (T283A) leads to larger GCs with increased DZ proliferation and, in older mice, clonal B cell lymphoproliferation, suggesting that the DZ inertial cell cycle program can be coopted by B cells undergoing malignant transformation.
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December 17 2020
Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells
Juhee Pae,
Juhee Pae
Formal analysis, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY
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Jonatan Ersching,
Jonatan Ersching
1
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY
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Tiago B.R. Castro,
Tiago B.R. Castro
Data curation, Formal analysis, Investigation, Methodology, Software
1
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY
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Marta Schips,
Marta Schips
Formal analysis
2
Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Luka Mesin,
Luka Mesin
Conceptualization, Investigation
1
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY
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Samuel J. Allon,
Samuel J. Allon
Investigation, Writing - review & editing
3
Institute for Medical Engineering and Science, Department of Chemistry, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
4
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, MA
5
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
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Jose Ordovas-Montanes,
Jose Ordovas-Montanes
Formal analysis, Investigation, Resources, Writing - review & editing
5
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
6
Division of Gastroenterology, Boston Children’s Hospital, Boston, MA
7
Program in Immunology Harvard Medical School, Boston, MA
8
Harvard Stem Cell Institute, Cambridge, MA
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Coraline Mlynarczyk,
Coraline Mlynarczyk
Investigation, Visualization, Writing - review & editing
9
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY
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Ari Melnick,
Ari Melnick
Formal analysis, Investigation, Writing - review & editing
9
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY
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Alejo Efeyan,
Alejo Efeyan
Investigation
10
Spanish National Cancer Research Center, Madrid, Spain
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Alex K. Shalek,
Alex K. Shalek
Conceptualization, Funding acquisition, Project administration, Supervision, Writing - original draft, Writing - review & editing
3
Institute for Medical Engineering and Science, Department of Chemistry, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
4
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, MA
5
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
7
Program in Immunology Harvard Medical School, Boston, MA
8
Harvard Stem Cell Institute, Cambridge, MA
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Michael Meyer-Hermann,
Michael Meyer-Hermann
Formal analysis, Funding acquisition, Project administration, Software, Writing - review & editing
2
Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
11
Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Braunschweig, Germany
12
Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
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Gabriel D. Victora
Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Visualization, Writing - original draft, Writing - review & editing
1
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY
Correspondence to Gabriel D. Victora: victora@rockefeller.edu
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Juhee Pae
Formal analysis, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY
Jonatan Ersching
1
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY
Tiago B.R. Castro
Data curation, Formal analysis, Investigation, Methodology, Software
1
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY
Marta Schips
Formal analysis
2
Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
Luka Mesin
Conceptualization, Investigation
1
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY
Samuel J. Allon
Investigation, Writing - review & editing
3
Institute for Medical Engineering and Science, Department of Chemistry, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
4
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, MA
5
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
Jose Ordovas-Montanes
Formal analysis, Investigation, Resources, Writing - review & editing
5
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
6
Division of Gastroenterology, Boston Children’s Hospital, Boston, MA
7
Program in Immunology Harvard Medical School, Boston, MA
8
Harvard Stem Cell Institute, Cambridge, MA
Coraline Mlynarczyk
Investigation, Visualization, Writing - review & editing
9
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY
Ari Melnick
Formal analysis, Investigation, Writing - review & editing
9
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY
Alejo Efeyan
Investigation
10
Spanish National Cancer Research Center, Madrid, Spain
Alex K. Shalek
Conceptualization, Funding acquisition, Project administration, Supervision, Writing - original draft, Writing - review & editing
3
Institute for Medical Engineering and Science, Department of Chemistry, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
4
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, MA
5
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA
7
Program in Immunology Harvard Medical School, Boston, MA
8
Harvard Stem Cell Institute, Cambridge, MA
Michael Meyer-Hermann
Formal analysis, Funding acquisition, Project administration, Software, Writing - review & editing
2
Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany
11
Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Braunschweig, Germany
12
Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
Gabriel D. Victora
Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Visualization, Writing - original draft, Writing - review & editing
1
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY
Correspondence to Gabriel D. Victora: victora@rockefeller.edu
Received:
August 07 2020
Revision Received:
November 16 2020
Accepted:
November 30 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
American Society of Hematology
(NO AWARD)
Burroughs Wellcome Fund
(NO AWARD)
Cancer Research Institute
(NO AWARD)
Damon Runyon Cancer Research Foundation
(DRG-2353-19, DRG-2274-16)
Horizon 2020 Framework Programme
(765158)
John D. and Catherine T. MacArthur Foundation
(NO AWARD)
Leukemia and Lymphoma Society
(NO AWARD)
Lymphoma Research Foundation
(NO AWARD)
Ministerio de Ciencia, Innovación y Universidades
(RYC-2013-13546)
National Cancer Institute
(R35CA220499)
National Institute of Allergy and Infectious Diseases
(R01AI119006, R01AI139117)
National Institutes of Health
(NO AWARD)
Pew Charitable Trusts
(NO AWARD)
Richard and Susan Smith Family Foundation
(NO AWARD)
Robertson Foundation
(NO AWARD)
Searle Scholars Program
(NO AWARD)
Starr Foundation
(I11-0027)
© 2020 Pae et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (4): e20201699.
Article history
Received:
August 07 2020
Revision Received:
November 16 2020
Accepted:
November 30 2020
Citation
Juhee Pae, Jonatan Ersching, Tiago B.R. Castro, Marta Schips, Luka Mesin, Samuel J. Allon, Jose Ordovas-Montanes, Coraline Mlynarczyk, Ari Melnick, Alejo Efeyan, Alex K. Shalek, Michael Meyer-Hermann, Gabriel D. Victora; Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells. J Exp Med 5 April 2021; 218 (4): e20201699. doi: https://doi.org/10.1084/jem.20201699
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