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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1804-1812.
Prepublished online as a Blood First Edition Paper on June 13, 2008; DOI 10.1182/blood-2008-01-136440.
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Submitted January 28, 2008
Accepted June 2, 2008
Spi-B inhibits human plasma cell differentiation by repressing BLIMP1 and XBP-1 expression
Heike Schmidlin, Sean A Diehl, Maho Nagasawa, Ferenc A Scheeren, Remko Schotte, Christel H Uittenbogaart, Hergen Spits, and Bianca Blom*
Departement of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
Departement of Microbiology, Immunology and Molecular Genetics, UCLA Center for the Health Sciences, Los Angeles, CA, United States
Department of Immunology, Genentech, South San Francisco, CA, United States
* Corresponding author; email: b.blom{at}amc.uva.nl.
The terminal differentiation of B cells into antibody-secreting plasma cells is tightly regulated by a complex network of transcription factors. Here we evaluated the role of the Ets factor Spi-B during terminal differentiation of human B cells. All mature tonsil and peripheral blood B cell subsets expressed Spi-B, with the exception of plasma cells. Overexpression of Spi-B in CD19+ B cells inhibited, similar to the known inhibitor BCL-6, the expression of plasma cell-associated surface markers and transcription factors as well as immunoglobulin production, i.e. in vitro plasma cell differentiation. The arrest in B cell differentiation enforced by Spi-B was independent of the transactivation domain, but dependent on the Ets-domain. By chromatin immunoprecipitation and assays utilizing an inducible Spi-B construct BLIMP1 and XBP-1 were identified as direct target genes of Spi-B mediated repression. We propose a novel role for Spi-B in maintenance of germinal center and memory B cells by direct repression of major plasma cell factors and thereby plasma cell differentiation.
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