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STAT5 regulates the self-renewal capacity and differentiation of human memory B cells and controls Bcl-6 expression

Nature Immunologyvolume 6pages303313 (2005) | Download Citation

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Abstract

It is unknown how B cells that mature during a germinal center reaction 'decide' between plasma or memory cell fate. Here we describe a previously unknown subpopulation of B cells in the human germinal center that is characterized by tyrosine phosphorylated transcriptional activator STAT5. These cells had an activated centrocyte phenotype and had abundant expression of BCL6 but low expression of PRDM1, both encoding transcriptional repression proteins. Using RNA interference and ectopic expression of constitutively activated forms of STAT5, we demonstrate here a function for STAT5 in the self-renewal of B cells in vitro. STAT5b isoform seemed to directly upregulate Bcl-6, and ectopic expression of Bcl-6 in B cells resulted in self-renewal and inhibition of plasma cell differentiation. These data indicate that activation of STAT5 is involved in regulation of memory B cell differentiation.

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Acknowledgements

We thank A. Bakker (Netherlands Cancer Institute, Amsterdam, Netherlands) for help in cloning; B. Hooibrink (Academic Medical Center, Amsterdam, Netherlands), A. Pfauth and F. van Diepen (Netherlands Cancer Institute, Amsterdam, Netherlands) for help with cell sorting; T. Dellemijn, L. Oomen and L. Brooks (Netherlands Cancer Institute, Amsterdam, Netherlands) for help with CLSM analyses of the tonsil sections and transduced B cell samples; N. van der Stoep (Leiden University Medical Center, Leiden, Netherlands) for help with the luciferase assays; and the Department of Otolaryngology, Academic Medical Center, Amsterdam, Netherlands (W. Fokkens) for providing tonsil tissue.

Author information

Author notes

  1. Ferenc A Scheeren and Marianne Naspetti: These authors contributed equally to this work.

Affiliations

  1. Department of Cell Biology and Histology of the Academic Medical Center, University of Amsterdam, Amsterdam, 1105, AZ, The Netherlands

    • Ferenc A Scheeren
    • , Sean Diehl
    • , Remko Schotte
    • , Maho Nagasawa
    • , Erwin Wijnands
    • , Ramon Gimeno
    • , Bianca Blom
    •  & Hergen Spits
  2. Division of Immunology, Netherlands Cancer Institute, Amsterdam, 1066, CX, The Netherlands

    • Ferenc A Scheeren
    • , Marianne Naspetti
    • , Remko Schotte
    • , Maho Nagasawa
    • , Florry A Vyth-Dreese
    • , Bianca Blom
    •  & Hergen Spits

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Competing interests

A patent has been filed (application PCT/5B2002/005753) based on the findings presented here and a company has been founded to commercialize the findings reported here.

Corresponding author

Correspondence to Hergen Spits.

Supplementary information

  1. Supplementary Fig. 1

    Flow cytometric analysis of a representative culture of CA-STAT5b-ER-IRES-ΔNGFR transduced B cells cultured in CD40L, IL-2 and IL-4 in the presence of 4HT. (PDF 219 kb)

  2. Supplementary Fig. 2

    Expression of WT-STAT5b-ER in IgG+ cells results in a 4HT dependent expansion in the presence of CD40L, IL-2 and IL-4. (PDF 83 kb)

  3. Supplementary Fig. 3

    Effect of BCL6 knock down on the growth of CA-STAT5b transduced B cells. (PDF 88 kb)

  4. Supplementary Fig. 4

    Activation of CA-STAT5-ER by 4HT upregulates MYC in transduced primary CD19+ cells. (PDF 106 kb)

  5. Supplementary Fig. 5

    Activation of CA-STAT5-ER by 4HT upregulates PAX5 in transduced primary CD19+ cells. (PDF 137 kb)

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https://doi.org/10.1038/ni1172

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