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Suppression of Signal Transducer and Activator of Transcription 3–Dependent B Lymphocyte Terminal Differentiation by Bcl-6

Reljic, Rajko, Wagner, Simon D., Peakman, Luke J., Fearon, Douglas T.·2000·The Journal of Experimental Medicine
DOI 10.1084/jem.192.12.1841
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Abstract

Lymphocytes usually differentiate into effector cells within days after antigen exposure, except in germinal centers where terminal differentiation is delayed while somatic hypermutation creates high-affinity antibody mutants. Here we investigate whether arrest of terminal differentiation can be mediated by BCL-6, a transcriptional repressor that is expressed by germinal center B cells and is required for this phase of B cell development. We find that BCL-6 suppresses the differentiation of transformed and primary B cells to plasma cells by inhibiting the signal transducer and activator of transcription 3–dependent expression of the major regulator of plasma cell development, the B lymphocyte–induced maturation protein (Blimp-1). This function of BCL-6 as a repressor of B lymphocyte differentiation may also underlie the association between chromosomal translocations of its gene and B cell lymphomas.

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Figure 1 The effect of BCL-6 on the growth and viability of BCL1 cells. (a) The number of viable BCL1 cells transduced with pHL6-GFP ( s , d ) or pHL6-BCL-6-GFP ( h , j ) was determined during culture in medium lacking ( s , h ) or containing IL-2 and IL-5 ( d , j ). (b) Cell cycle analysis of BCL1 cells cultured for 4 d in the absence or presence of cytokines was performed by flow cytometry after staining with propidium iodide. (c) Binding of annexin V to BCL1 cells cultured for 3 d in the absence or presence of cytokines was measured by flow cytometry.
Figure 1 The effect of BCL-6 on the growth and viability of BCL1 cells. (a) The number of viable BCL1 cells transduced with pHL6-GFP ( s , d ) or pHL6-BCL-6-GFP ( h , j ) was determined during culture in medium lacking ( s , h ) or containing IL-2 and IL-5 ( d , j ). (b) Cell cycle analysis of BCL1 cells cultured for 4 d in the absence or presence of cytokines was performed by flow cytometry after staining with propidium iodide. (c) Binding of annexin V to BCL1 cells cultured for 3 d in the absence or presence of cytokines was measured by flow cytometry.CC-BY-NC-SA · From the PDF
Figure 2 The effect of BCL-6 on cytokine-induced differentiation of BCL1 cells. (a) The secretion of IgM by BCL1 cells transduced with pHL6-GFP ( s , d ) or pHL6-BCL-6-GFP ( h , j ) during culture in medium lacking ( s , h ) or containing IL-2 and IL-5 ( d , j ) was measured by ELISA. (b) The expression of J chain mRNA in transduced cells cultured for 3 d in the absence or presence of cytokines was assessed by RTPCR. (c) The expression of Blimp-1 in transduced BCL1 cells cultured for 3 d in the absence or presence of cytokines was assessed by Western blot analysis.
Figure 2 The effect of BCL-6 on cytokine-induced differentiation of BCL1 cells. (a) The secretion of IgM by BCL1 cells transduced with pHL6-GFP ( s , d ) or pHL6-BCL-6-GFP ( h , j ) during culture in medium lacking ( s , h ) or containing IL-2 and IL-5 ( d , j ) was measured by ELISA. (b) The expression of J chain mRNA in transduced cells cultured for 3 d in the absence or presence of cytokines was assessed by RTPCR. (c) The expression of Blimp-1 in transduced BCL1 cells cultured for 3 d in the absence or presence of cytokines was assessed by Western blot analysis.CC-BY-NC-SA · From the PDF
Figure 3 The effect of Blimp-1 on the growth and viability of BCL1 cells. BCL1 cells lacking ( s , d ) or expressing BCL-6 ( h , j ) were transduced with pHL6-GFP ( s , h ) or pHL6-Blimp-1-GFP ( d , j ). The fraction of viable cells that were GFP 1 , relative to day 2 after transduction, was determined.
Figure 3 The effect of Blimp-1 on the growth and viability of BCL1 cells. BCL1 cells lacking ( s , d ) or expressing BCL-6 ( h , j ) were transduced with pHL6-GFP ( s , h ) or pHL6-Blimp-1-GFP ( d , j ). The fraction of viable cells that were GFP 1 , relative to day 2 after transduction, was determined.CC-BY-NC-SA · From the PDF
Figure 4 The effect of BCL-6 on the differentiation of primary B cells. (a) Primary B cells transduced with pHL6-GFP or pHL6-BCL-6GFP were cultured in the presence of CD40 ligand and IL-2, -4, -7, and -15, and GFP 1 cells were assessed for expression of syndecan 1 by flow cytometry. (b) The secretion of IgM, IgG1, and IgA by flow-sorted primary B cells transduced with pHL6-GFP or pHL6-BCL-6-GFP after culture for 5 d in the presence of CD40 ligand and IL-2, -4, -7, and -15 was measured by ELISA. (c) The expression of Blimp-1 mRNA relative to HPRT mRNA by flow-sorted primary B cells, which had been transduced with pHL6-GFP or pHL6-BCL-6-GFP and cultured with CD40 ligand and IL-2, -4, -7, and -15, was determined on day 5.
Figure 4 The effect of BCL-6 on the differentiation of primary B cells. (a) Primary B cells transduced with pHL6-GFP or pHL6-BCL-6GFP were cultured in the presence of CD40 ligand and IL-2, -4, -7, and -15, and GFP 1 cells were assessed for expression of syndecan 1 by flow cytometry. (b) The secretion of IgM, IgG1, and IgA by flow-sorted primary B cells transduced with pHL6-GFP or pHL6-BCL-6-GFP after culture for 5 d in the presence of CD40 ligand and IL-2, -4, -7, and -15 was measured by ELISA. (c) The expression of Blimp-1 mRNA relative to HPRT mRNA by flow-sorted primary B cells, which had been transduced with pHL6-GFP or pHL6-BCL-6-GFP and cultured with CD40 ligand and IL-2, -4, -7, and -15, was determined on day 5.CC-BY-NC-SA · From the PDF
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Research works printed but not linked: 30

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Cited by

Metadata

Authors
Reljic, R., Wagner, S. D., Peakman, L. J., & Fearon, D. T.
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2000-12-18
Volume
192
Issue
12
Pages
1841-1848
ISSN
  • 0022-1007
  • 1540-9538
DOI
10.1084/jem.192.12.1841
Cited by
182
References
0
Language
en

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