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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Ahmed, R. & Gray, D. Immunological memory and protective immunity: understanding their relation. Science 272, 54–60 (1996).
DalPorto, J. M., Haberman, A. M., Shlomchik, M. J. & Kelsoe, G. Antigen drives very low affinity B cells to become plasmacytes and enter germinal centers. J. Immunol. 161, 5373–5381 (1998).
Arpin, C. et al. Generation of memory B cells and plasma cells in vitro. Science 268, 720–722 (1995).
Foy, T. M., Aruffo, A., Bajorath, J., Buhlmann, J. E. & Noelle, R. J. Immune regulation by CD40 and its ligand GP39. Annu. Rev. Immunol. 14, 591–617 (1996).
Randall, T. D. et al. Interleukin-5 (IL-5) and IL-6 define two molecularly distinct pathways of B-cell differentiation. Mol. Cell. Biol. 13, 3929–3936 (1993).
Takatsu, K. Cytokines involved in B-cell differentiation and their sites of action. Proc. Soc. Exp. Biol. Med. 215, 121–133 (1997).
Altmeyer, A. et al. Reversal of EBV immortalization precedes apoptosis in IL-6-induced human B cell terminal differentiation. Immunity 7, 667–677 (1997).
Illera, V. A., Perandones, C. E., Stunz, L. L., Mower, D. A. Jr & Ashman, R. F. Apoptosis in splenic B lymphocytes. Regulation by protein kinase C and IL-4. J. Immunol. 151, 2965–2973 (1993).
Choe, J. & Choi, Y. S. IL-10 interrupts memory B cell expansion in the germinal center by inducing differentiation into plasma cells. Eur. J. Immunol. 28, 508–515 (1998).
Liu, Y. J. & Banchereau, J. Regulation of B-cell commitment to plasma cells or to memory B cells. Semin. Immunol. 9, 235–240 (1997).
McHeyzer-Williams, M. G. & Ahmed, R. B cell memory and the long-lived plasma cell. Curr. Opin. Immunol. 11, 172–179 (1999).
Morse, L., Chen, D., Franklin, D., Xiong, Y. & Chen-Kiang, S. Induction of cell cycle arrest and B cell terminal differentiation by CDK inhibitor p18INK4c and IL-6. Immunity 6, 47–56 (1997).
Kopf, M. et al. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368, 339–342 (1994).
Henderson, A. & Calame, K. Transcriptional regulation during B cell development. Annu. Rev. Immunol. 16, 163–200 (1998).
Glimcher, L. H. & Singh, H. Transcription factors in lymphocyte development—T and B cells get together. Cell 96, 13–23 (1999).
Oliver, A. M., Martin, F. & Kearney, J. F. Mouse CD38 is down-regulated on germinal center B cells and mature plasma cells. J. Immunol. 158, 1108–1115 (1997).
Morrison, A. M., Nutt, S. L., Thevenin, C., Tolink, A. & Busslinger, M. Loss- and gain-of-function mutations reveal an important role of BSAP (Pax-5) at the start and end of B cell differentiation. Semin. Immunol. 10, 133–142 (1998).
Schliephake, D. E. & Schimpl, A. Blimp-1 overcomes the block in IgM secretion in lipopolysaccharide/anti-mu F(ab′)2-co-stimulated B lymphocytes. Eur. J. Immunol. 26, 268–271 (1996).
Turner, C. A. Jr, Mack, D. H. & Davis, M. M. Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell 77, 297–306 (1994).
Angelin-Duclos, C., Cattoretti, G., Lin, K.-I. & Calame, K. Commitment of B lymphocytes to a plasma cell fate is associated with Blimp-1 expression in vivo. J. Immunol. 165, 5462–5471 (2000).
Lin, Y., Wong, K.-K. & Calame, K. Repression of c-myc transcription by Blimp-1, an inducer of terminal B cell differentiation. Science 276, 596–599 (1997).
Melchers, F. B-lymphocyte-lineage cells from early precursors to Ig-secreting plasma cells: targets of regulation by the myc/mad/max families of genes? Curr. Top. Microbiol. Immunol. 224, 19–30 (1997).
Yu, J., Angelin-Duclos, C., Greenwood, J., Liao, J. & Calame, K. Transcriptional repression by Blimp-1 (PRDI-BF1) involves recruitment of histone deacetylase. Mol. Cell. Biol. 20, 2592–2603 (2000).
Liou, H. C. et al. A new member of the leucine zipper class of proteins that binds to the HLA DR alpha promoter. Science 247, 1581–1584 (1990).
Clauss, I. M. et al. In situ hybridization studies suggest a role for the basic region-leucine zipper protein hXBP-1 in exocrine gland and skeletal development during mouse embryogenesis. Dev. Dynam. 197, 146–156 (1993).
Gravallese, E. M., Darling, J. M., Ladd, A. L., Katz, J. N. & Glimcher, L. H. In situ hybridization studies of stromelysin and collagenase mRNA expression in rheumatoid synovium. Arthritis Rheum. 34, 1076–1084 (1991).
Reimold, A. M. et al. An essential role in liver development for transcription factor XBP-1. Genes Dev. 14, 152–157 (2000).
Wen, X. Y. et al. Identification of c-myc promoter-binding protein and X-box binding protein 1 as interleukin-6 target genes in human multiple myeloma cells. Int. J. Oncol. 15, 173–178 (1999).
Reimold, A. M. et al. Transcription factor B cell lineage-specific activator protein regulates the gene for human X-box binding protein 1. J. Exp. Med. 183, 393–401 (1996).
Chen, J., Lansford, R., Stewart, V., Young, F. & Alt, F. W. RAG-2-deficient blastocyst complementation: an assay of gene function in lymphocyte development. Proc. Natl Acad. Sci. USA 90, 4528–4532 (1993).
Kim, H. J., Krenn, V., Steinhauser, G. & Berek, C. Plasma cell development in synovial germinal centers in patients with rheumatoid and reactive arthritis. J. Immunol. 162, 3053–3062 (1999).
Blackman, M. A., Tigges, M. A., Minie, M. E. & Koshland, M. E. A model system for peptide hormone action in differentiation: interleukin 2 induces a B lymphoma to transcribe the J chain gene. Cell 47, 609–617 (1986).
Brooks, K., Yuan, D., Uhr, J. W., Krammer, P. H. & Vitetta, E. S. Lymphokine-induced IgM secretion by clones of neoplastic B cells. Nature 302, 825–826 (1983).
Franzoso, G. et al. Mice deficient in nuclear factor (NF)-kappa B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture. J. Exp. Med. 187, 147–159 (1998).
Mittrucker, H. W. et al. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275, 540–543 (1997).
Schwarz, E. M., Krimpenfort, P., Berns, A. & Verma, I. M. Immunological defects in mice with a targeted disruption in Bcl-3. Genes Dev. 11, 187–197 (1997).
Dent, A. L., Shaffer, A. L., Yu, X., Allman, D. & Staudt, L. M. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 276, 589–592 (1997).
Sanderson, R. D., Lalor, P. & Bernfield, M. B lymphocytes express and lose syndecan at specific stages of differentiation. Cell Regul. 1, 27–35 (1989).
Bachmann, M. F. & Kopf, M. The role of B cells in acute and chronic infections. Curr. Opin. Immunol. 332–339 (1999).
Szomolanyi-Tsuda, E. & Welsh, R. M. T cell-independent antibody-mediated clearance of polyoma virus in T cell-deficient mice. J. Exp. Med. 183, 403–411 (1996).
Messika, E. J. et al. Differentiated effect of B lymphocyte-induced maturation protein (Blimp-1) expression on cell fate during B cell development. J. Exp. Med. 188, 515–525 (1998).
Knodel, M., Kuss, A. W., Lindemann, D., Berberich, I. & Schimpl, A. Reversal of Blimp-1-mediated apoptosis by A1, a member of the Bcl-2 family. Eur. J. Immunol. 29, 2988–2998 (1999).
Lin, K.-I., Lin, Y. & Calame, K. Repression of c-myc is necessary but not sufficient for terminal differentiation of B lymphocytes in vitro. Mol. Cell. Biol. 20, 8684–8695 (2000).
Soro, P. G. et al. Differential involvement of the transcription factor blimp-1 in T cell-independent and -dependent B cell differentiation to plasma cells. J. Immunol. 163, 611–617 (1999).
Hodge, M. R. et al. Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice. Immunity 4, 397–405 (1996).
Szabo, S. J. et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655–669 (2000).
Manis, J. P. et al. Class switching in B cells lacking 3′ immunoglobulin heavy chain enhancers. J. Exp. Med. 188, 1421–1431 (1998).
Gartner, F., Alt, F. W., Monroe, R. J. & Seidl, K. J. Antigen-independent appearance of recombination activating gene (RAG)-positive bone marrow B cells in the spleens of immunized mice. J. Exp. Med. 192, 1745–1754 (2000).
Szomolanyi-Tsuda, E., Brien, J. D., Dorgan, J. E., Welsh, R. M. & Garcea, R. L. The role of CD40–CD154 interaction in antiviral T cell-independent IgG responses. J. Immunol. 164, 5877–5882.
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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