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Plasma cell differentiation requires the transcription factor XBP-1

Abstract

Considerable progress has been made in identifying the transcription factors involved in the early specification of the B-lymphocyte lineage. However, little is known about factors that control the transition of mature activated B cells to antibody-secreting plasma cells. Here we report that the transcription factor XBP-1 is required for the generation of plasma cells. XBP-1 transcripts were rapidly upregulated in vitro by stimuli that induce plasma-cell differentiation, and were found at high levels in plasma cells from rheumatoid synovium. When introduced into B-lineage cells, XBP-1 initiated plasma-cell differentiation. Mouse lymphoid chimaeras deficient in XBP-1 possessed normal numbers of activated B lymphocytes that proliferated, secreted cytokines and formed normal germinal centres. However, they secreted very little immunoglobulin of any isotype and failed to control infection with the B-cell-dependent polyoma virus, because plasma cells were markedly absent. XBP-1 is the only transcription factor known to be selectively and specifically required for the terminal differentiation of B lymphocytes to plasma cells.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (L.H.G., F.A. and A.R.) and the Hood Foundation (J.M.), and a gift from the G. Harold and Leila Y. Mathers Charitable Foundation (L.H.G.). We thank A. Erlebacher, K. Mowen and S. Peng for a review of the manuscript; L. Davidson and K. Sigrist for production of XBP/RAG-/- chimaeras; M. Wheaton for technical assistance with the polyoma virus experiments; C. McCall for preparation of the manuscript; and A. Bottaro and I. Kuzin for IgM primers.

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Correspondence to Laurie H. Glimcher.

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Further reading

Figure 1: XBP-1 expression in rheumatoid synovium.
Figure 2: Induction of XBP-1 is upstream and downstream of signals that drive plasma-cell differentiation.
Figure 3: Gene targeting to generate XBP-1-deficient cells.
Figure 4: XBP-1 is required for immunoglobulin secretion.
Figure 5
Figure 6: In vitro phenotype of XBP-1-/- B cells.
Figure 7: Decreased formation of plasma cells in the absence of XBP-1.
Figure 8: XBP-1-/- lymphocytes do not respond to T-cell-independent or -dependent antigens or to polyoma virus in vivo.

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