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  • Review Article
  • Published:

Regulation of plasma-cell development

Nature Reviews Immunology volume 5, pages 230–242 (2005)Cite this article

Key Points

  • Plasma cells are the final effectors of the B-cell lineage. After activation by antigen, in the presence of T-cell help when required, naive B cells in the marginal zone and follicles rapidly develop into short-lived plasma cells. Follicular B cells can also undergo a germinal-centre reaction, and after proliferation, affinity maturation and class-switch recombination, both memory B cells and plasma cells are formed.

  • The transcriptional mechanisms that are required for activated B cells and plasma cells are different and seem to be mutually exclusive. In activated B cells, BCL-6 (B-cell lymphoma 6), MTA3 (metastasis-associated 1 family, member 3), PAX5 (paired box protein 5) and MITF (microphthalmia-associated transcription factor) are important: in addition to inducing B-cell gene-expression programmes, they repress plasma-cell formation. In plasma cells, BLIMP1 (B-lymphocyte-induced maturation protein 1), XBP1 (X-box-binding protein 1) and IRF4 (interferon-regulatory factor 4) are important: they repress the B-cell gene-expression programme.

  • The roles and regulation of these transcription factors are reviewed. Recent experiments show that plasma cells require the continued presence of BLIMP1 and XBP1 and the continued absence of BCL-6 and MTA3. If the levels of these factors are altered, plasma cells either die or dedifferentiate.

  • BLIMP1 and XBP1 are required for immunoglobulin secretion by plasma cells. BLIMP1 regulates the μM (transmembrane form of μ immunoglobulin heavy chain) to μS (secreted form) mRNA switch and, by repression of PAX5, it derepresses transcription of the genes that encode the immunoglobulin heavy chain, the immunoglobulin light chain and XBP1, which are required for organelle biogenesis, endoplasmic-reticulum function, protein folding and protein secretion.

  • Post-germinal-centre plasma cells that migrate to the bone marrow survive and continue to secrete immunoglobulin for prolonged periods. The chemokines, integrins, selectins and cytokines that are required for plasma-cell survival are discussed.

Abstract

Plasma cells are the terminally differentiated, non-dividing effector cells of the B-cell lineage. They are cellular factories devoted to the task of synthesizing and secreting thousands of molecules of clonospecific antibody each second. To respond to microbial pathogens with the necessary specificity and rapidity, B cells are exquisitely regulated with respect to both development in the bone marrow and activation in the periphery. This review focuses on the terminal differentiation of B cells into plasma cells, including the different subsets of B cells that become plasma cells, the mechanism of regulation of this transition, the transcription factors that control each developmental stage and the characteristics of long-lived plasma cells.

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Figure 1: Antigen-independent development of B cells.
Figure 2: Formation of plasma cells.
Figure 3: Transcriptional repression inforces mutually exclusive B-cell and plasma-cell gene-expression programmes.
Figure 4: Gene regulation in germinal-centre B cells and plasma cells.
Figure 5: Gene expression in immunoglobulin-secreting plasma cells is regulated by BLIMP1 and XBP1.
Figure 6: Long-lived plasma cells in the bone marrow.

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References

  1. Busslinger, M. Transcriptional control of early B cell development. Annu. Rev. Immunol. 22, 55–79 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Krangel, M. S. Gene segment selection in V(D)J recombination: accessibility and beyond. Nature Immunol. 4, 624–630 (2003).

    Article  CAS  Google Scholar 

  3. Ohashi, P. S. & DeFranco, A. L. Making and breaking tolerance. Curr. Opin. Immunol. 14, 744–759 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Hardy, R. R. & Hayakawa, K. B cell development pathways. Annu. Rev. Immunol. 19, 595–621 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Chung, J. B., Silverman, M. & Monroe, J. G. Transitional B cells: step by step towards immune competence. Trends Immunol. 24, 343–349 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Pillai, S., Cariappa, A. & Moran, S. T. Marginal zone B cells. Annu. Rev. Immunol. 20 Oct 2004 (10.1146/annurev.immunol.23.021704.115728).

  7. Lopes-Carvalho, T. & Kearney, J. F. Development and selection of marginal zone B cells. Immunol. Rev. 197, 192–205 (2004).

    Article  PubMed  Google Scholar 

  8. Tanigaki, K. et al. Notch–RBP-J signaling is involved in cell fate determination of marginal zone B cells. Nature Immunol. 3, 443–450 (2002).

    Article  CAS  Google Scholar 

  9. Oliver, A. M., Martin, F., Gartland, G. L., Carter, R. H. & Kearney, J. F. Marginal zone B cells exhibit unique activation, proliferative and immunoglobulin secretory responses. Eur. J. Immunol. 27, 2366–2374 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Oliver, A. M., Martin, F. & Kearney, J. F. IgMhighCD21high lymphocytes enriched in the splenic marginal zone generate effector cells more rapidly than the bulk of follicular B cells. J. Immunol. 162, 7198–7207 (1999).

    CAS  PubMed  Google Scholar 

  11. Jacob, J., Kassir, R. & Kelsoe, G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. I. The architecture and dynamics of responding cell populations. J. Exp. Med. 173, 1165–1175 (1991).

    Article  CAS  PubMed  Google Scholar 

  12. Smith, K. G., Hewitson, T. D., Nossal, G. J. & Tarlinton, D. M. The phenotype and fate of the antibody-forming cells of the splenic foci. Eur. J. Immunol. 26, 444–448 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. McHeyzer-Williams, L. J., Driver, D. J. & McHeyzer-Williams, M. G. Germinal center reaction. Curr. Opin. Hematol. 8, 52–59 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. McHeyzer-Williams, M. G. B cells as effectors. Curr. Opin. Immunol. 15, 354–361 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Manser, T. Textbook germinal centers? J. Immunol. 172, 3369–3375 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Bishop, G. A. & Hostager, B. S. Signaling by CD40 and its mimics in B cell activation. Immunol. Res. 24, 97–109 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Kim, C. H. et al. Unique gene expression program of human germinal center T helper cells. Blood 104, 1952–1960 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Crotty, S., Kersh, E. N., Cannons, J., Schwartzberg, P. L. & Ahmed, R. SAP is required for generating long-term humoral immunity. Nature 421, 282–287 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Barrington, R. A., Pozdnyakova, O., Zafari, M. R., Benjamin, C. D. & Carroll, M. C. B lymphocyte memory: role of stromal cell complement and FcγRIIB receptors. J. Exp. Med. 196, 1189–1199 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. McHeyzer-Williams, M. G. & Ahmed, R. B cell memory and the long-lived plasma cell. Curr. Opin. Immunol. 11, 172–179 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Maruyama, M., Lam, K. P. & Rajewsky, K. Memory B-cell persistence is independent of persisting immunizing antigen. Nature 407, 636–642 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Tangye, S. G., Avery, D. T., Deenick, E. K. & Hodgkin, P. D. Intrinsic differences in the proliferation of naive and memory human B cells as a mechanism for enhanced secondary immune responses. J. Immunol. 170, 686–694 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Bernasconi, N. L., Traggiai, E. & Lanzavecchia, A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science 298, 2199–2202 (2002). This paper showed that bystander T-cell help and CpG oligodeoxynucleotides can activate human memory B cells in an antigen-independent manner.

    Article  CAS  PubMed  Google Scholar 

  24. McHeyzer-Williams, L. J., Cool, M. & McHeyzer-Williams, M. G. Antigen-specific B cell memory: expression and replenishment of a novel B220− memory B cell compartment. J. Exp. Med. 191, 1149–1166 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bell, J. & Gray, D. Antigen-capturing cells can masquerade as memory B cells. J. Exp. Med. 197, 1233–1244 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. O'Connor, B. P., Cascalho, M. & Noelle, R. J. Short-lived and long-lived bone marrow plasma cells are derived from a novel precursor population. J. Exp. Med. 195, 737–745 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shapiro-Shelef, M. et al. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory cells. Immunity 19, 607–620 (2003). In this study, mice with a B-cell-specific deletion of the gene that encodes BLIMP1 were created, and it was shown that BLIMP1 is required for plasma-cell formation and immunoglobulin secretion.

    Article  CAS  PubMed  Google Scholar 

  28. Hasbold, J., Corcoran, L. M., Tarlinton, D. M., Tangye, S. G. & Hodgkin, P. D. Evidence from the generation of immunoglobulin G-secreting cells that stochastic mechanisms regulate lymphocyte differentiation. Nature Immunol. 5, 55–63 (2004). In this study, a division-tracking dye and stimulation of B cells in vitro were used, and it was shown that, at each cell division, there is a probability of plasmacytic differentiation.

    Article  CAS  Google Scholar 

  29. Tangye, S. G. & Hodgkin, P. D. Divide and conquer: the importance of cell division in regulating B-cell responses. Immunology 112, 509–520 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nutt, S. L., Eberhard, D., Horcher, M., Rolink, A. G. & Busslinger, M. Pax5 determines the identity of B cells from the beginning to the end of B-lymphopoiesis. Int. Rev. Immunol. 20, 65–82 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Lin, K. I., Angelin-Duclos, C., Kuo, T. C. & Calame, K. Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Mol. Cell. Biol. 22, 4771–4780 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Horcher, M., Souabni, A. & Busslinger, M. Pax5/BSAP maintains the identity of B cells in late B lymphopoiesis. Immunity 14, 779–790 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Gonda, H. et al. The balance between Pax5 and Id2 activities is the key to AID gene expression. J. Exp. Med. 198, 1427–1437 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    Article  CAS  PubMed  Google Scholar 

  35. Rinkenberger, J. L., Wallin, J. J., Johnson, K. W. & Koshland, M. E. An interleukin-2 signal relieves BSAP (Pax5)-mediated repression of the immunoglobulin J chain gene. Immunity 5, 377–386 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Singh, M. & Birshtein, B. K. NF-HB (BSAP) is a repressor of the murine immunoglobulin heavy-chain 3′α enhancer at early stages of B-cell differentiation. Mol. Cell. Biol. 13, 3611–3622 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shaffer, A. L., Peng, A. & Schlissel, M. S. In vivo occupancy of the κ light chain enhancers in primary pro- and pre-B cells: a model for κ locus activation. Immunity 6, 131–143 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Lin, L., Gerth, A. J. & Peng, S. L. Active inhibition of plasma cell development in resting B cells by microphthalmia-associated transcription factor. J. Exp. Med. 200, 115–122 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cattoretti, G. et al. BCL-6 protein is expressed in germinal-center B cells. Blood 86, 45–53 (1995).

    CAS  PubMed  Google Scholar 

  40. 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).

    Article  CAS  PubMed  Google Scholar 

  41. Shaffer, A. L. et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13, 199–212 (2000). In this study, microarray analyses were used to identify direct targets of BCL-6, including the gene encoding BLIMP1.

    Article  CAS  PubMed  Google Scholar 

  42. Fearon, D. T., Manders, P. M. & Wagner, S. D. Bcl-6 uncouples B lymphocyte proliferation from differentiation. Adv. Exp. Med. Biol. 512, 21–28 (2002).

    Article  PubMed  Google Scholar 

  43. Tunyaplin, C. et al. Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J. Immunol. 173, 1158–1165 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Vasanwala, F. H., Kusam, S., Toney, L. M. & Dent, A. L. Repression of AP-1 function: a mechanism for the regulation of Blimp-1 expression and B lymphocyte differentiation by the B cell lymphoma-6 protooncogene. J. Immunol. 169, 1922–1929 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Reljic, R., Wagner, S. D., Peakman, L. J. & Fearon, D. T. Suppression of signal transducer and activator of transcription 3-dependent B lymphocyte terminal differentiation by BCL-6. J. Exp. Med. 192, 1841–1848 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Phan, R. T. & Dalla-Favera, R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 432, 635–639 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Fujita, N. et al. MTA3 and the Mi-2/NuRD complex regulate cell fate during B lymphocyte differentiation. Cell 119, 75–86 (2004). This paper showed that MTA3 is required for BCL-6 activity and that, when both MTA3 and BCL-6 are expressed by plasmacytomas, the immunoglobulin-secretion phenotype can be reversed.

    Article  CAS  PubMed  Google Scholar 

  48. Muto, A. et al. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 429, 566–571 (2004). This paper showed that BACH2 is required for the germinal-centre reaction and that it might inhibit plasmacytic differentiation.

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    Article  CAS  PubMed  Google Scholar 

  50. 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).

    Article  CAS  PubMed  Google Scholar 

  51. Kallies, A. et al. Plasma cell ontogeny defined by quantitative changes in Blimp-1 expression. J. Exp. Med. 200, 967–977 (2004). In this study, a knock-in of the gene encoding green fluorescent protein into the Prdm1 locus provided a way to measure BLIMP1 expression during B-cell development and showed that all BLIMP1+ B cells secrete immunoglobulin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lin, Y., Wong, K. & Calame, K. Repression of c-myc transcription by Blimp-1, an inducer of terminal B cell differentiation. Science 276, 596–599 (1997).

    Article  CAS  PubMed  Google Scholar 

  53. Shaffer, A. L. et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17, 51–62 (2002). In this study, microarray analyses of human B-cell lines that ectopically express BLIMP1 allowed the identification of multiple genes that are regulated by BLIMP1. These could be divided into three categories on the basis of their function: repression of proliferation, induction of immunoglobulin secretion and repression of B-cell functions.

    Article  CAS  PubMed  Google Scholar 

  54. Shaffer, A. L. et al. XBP1 acts downstream of Blimp-1 to expand the secretory apparatus, promote organelle biogenesis, and increase protein synthesis during plasma cell differentiation. Immunity 21, 81–93 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Sciammas, R. & Davis, M. M. Modular nature of Blimp-1 in the regulation of gene expression during B cell maturation. J. Immunol. 172, 5427–5440 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Reimold, A. M. et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature 412, 300–307 (2001). In this study, recombination-activating gene 1 (RAG1)-deficient blastocyst complementation was used to identify the transcriptional activator XBP1 as the first transcriptional regulator known to be required for plasma-cell formation.

    Article  CAS  PubMed  Google Scholar 

  57. Mittrucker, H. W. et al. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275, 540–543 (1997).

    Article  CAS  PubMed  Google Scholar 

  58. Falini, B. et al. A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal center B cells, plasma cells, and activated T cells. Blood 95, 2084–2092 (2000).

    CAS  PubMed  Google Scholar 

  59. Eisenbeis, C. F., Singh, H. & Storb, U. Pip, a novel IRF family member, is a lymphoid-specific, PU.1-dependent transcriptional activator. Genes Dev. 9, 1377–1387 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Pongubala, J. M. & Atchison, M. L. PU.1 can participate in an active enhancer complex without its transcriptional activation domain. Proc. Natl Acad. Sci. USA 94, 127–132 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Allman, D. et al. BCL-6 expression during B-cell activation. Blood 87, 5257–5268 (1996).

    CAS  PubMed  Google Scholar 

  62. Niu, H., Ye, B. H. & Dalla-Favera, R. Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev. 12, 1953–1961 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Muto, A. et al. Identification of Bach2 as a B-cell-specific partner for small Maf proteins that negatively regulate the immunoglobulin heavy chain gene 3′ enhancer. EMBO J. 17, 5734–5743 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Schliephake, D. E. & Schimpl, A. Blimp-1 overcomes the block in IgM secretion in lipopolysaccharide/anti-μ F(ab′)2-co-stimulated B lymphocytes. Eur. J. Immunol. 26, 268–271 (1996).

    Article  CAS  PubMed  Google Scholar 

  65. Snapper, C. M., Kehry, M. R., Castle, B. E. & Mond, J. J. Multivalent, but not divalent, antigen receptor cross-linkers synergize with CD40 ligand for induction of Ig synthesis and class switching in normal murine B cells. A redefinition of the TI-2 vs T cell-dependent antigen dichotomy. J. Immunol. 154, 1177–1187 (1995).

    CAS  PubMed  Google Scholar 

  66. McHeyzer-Williams, L. J. & McHeyzer-Williams, M. G. Developmentally distinct TH cells control plasma cell production in vivo. Immunity 20, 231–242 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Gantner, F. et al. CD40-dependent and -independent activation of human tonsil B cells by CpG oligodeoxynucleotides. Eur. J. Immunol. 33, 1576–1585 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Takeda, K. & Akira, S. TLR signaling pathways. Semin. Immunol. 16, 3–9 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Piskurich, J. F. et al. BLIMP-1 mediates extinction of major histocompatibility class II transactivator expression in plasma cells. Nature Immunol. 1, 526–532 (2000).

    Article  CAS  Google Scholar 

  70. 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).

    CAS  PubMed  Google Scholar 

  71. Ozaki, K. et al. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J. Immunol. 173, 5361–5371 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Fearon, D. T., Manders, P. & Wagner, S. D. Arrested differentiation, the self-renewing memory lymphocyte, and vaccination. Science 293, 248–250 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Singh, M. & Birshtein, B. K. Concerted repression of an immunoglobulin heavy-chain enhancer, 3′αE(hs1,2). Proc. Natl Acad. Sci. USA 93, 4392–4397 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Andersson, T., Samuelsson, A., Matthias, P. & Pettersson, S. The lymphoid-specific cofactor OBF-1 is essential for the expression of a VH promoter/HS1,2 enhancer-linked transgene in late B cell development. Mol. Immunol. 37, 889–899 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Casellas, R. et al. OcaB is required for normal transcription and V(D)J recombination of a subset of immunoglobulin κ genes. Cell 110, 575–585 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Peterson, M. L., Bertolino, S. & Davis, F. An RNA polymerase pause site is associated with the immunoglobulin μs poly(A) site. Mol. Cell. Biol. 22, 5606–5615 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Veraldi, K. L. et al. hnRNP F influences binding of a 64-kilodalton subunit of cleavage stimulation factor to mRNA precursors in mouse B cells. Mol. Cell. Biol. 21, 1228–1238 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Early, P. et al. Two mRNAs can be produced from a single immunoglobulin μ gene by alternative RNA processing pathways. Cell 20, 313–319 (1980).

    Article  CAS  PubMed  Google Scholar 

  79. Rogers, J. et al. Two mRNAs with different 3′ ends encode membrane-bound and secreted forms of immunoglobulin μ chain. Cell 20, 303–312 (1980).

    Article  CAS  PubMed  Google Scholar 

  80. Harding, H. P., Calfon, M., Urano, F., Novoa, I. & Ron, D. Transcriptional and translational control in the mammalian unfolded protein response. Annu. Rev. Cell Dev. Biol. 18, 575–599 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Gass, J. N., Gunn, K. E., Sriburi, R. & Brewer, J. W. Stressed-out B cells? Plasma-cell differentiation and the unfolded protein response. Trends Immunol. 25, 17–24 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Gass, J. N., Gifford, N. M. & Brewer, J. W. Activation of an unfolded protein response during differentiation of antibody-secreting B cells. J. Biol. Chem. 277, 49047–49054 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Calfon, M. et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415, 92–96 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Iwakoshi, N. N. et al. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nature Immunol. 4, 321–329 (2003).

    Article  CAS  Google Scholar 

  85. Yoshida, H. et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol. Cell. Biol. 20, 6755–6767 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. van Anken, E. et al. Sequential waves of functionally related proteins are expressed when B cells prepare for antibody secretion. Immunity 18, 243–253 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Vieira, P. & Rajewsky, K. The half-lives of serum immunoglobulins in adult mice. Eur. J. Immunol. 18, 313–316 (1988).

    Article  CAS  PubMed  Google Scholar 

  88. Slifka, M. K., Matloubian, M. & Ahmed, R. Bone marrow is a major site of long-term antibody production after acute viral infection. J. Virol. 69, 1895–1902 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Manz, R. A., Thiel, A. & Radbruch, A. Lifetime of plasma cells in the bone marrow. Nature 388, 133–134 (1997).

    Article  CAS  PubMed  Google Scholar 

  90. Slifka, M. K., Antia, R., Whitmire, J. K. & Ahmed, R. Humoral immunity due to long-lived plasma cells. Immunity 8, 363–372 (1998). In this study, adoptive transfer of antigen-specific plasma cells to naive mice was used to show that long-lived plasma cells survive and secrete antibody for more than 1 year, and this occurs in the absence of any detectable memory cells.

    Article  CAS  PubMed  Google Scholar 

  91. Manz, R. A., Lohning, M., Cassese, G., Thiel, A. & Radbruch, A. Survival of long-lived plasma cells is independent of antigen. Int. Immunol. 10, 1703–1711 (1998).

    Article  CAS  PubMed  Google Scholar 

  92. Sze, D. M., Toellner, K. M., Garcia de Vinuesa, C., Taylor, D. R. & MacLennan, I. C. Intrinsic constraint on plasmablast growth and extrinsic limits of plasma cell survival. J. Exp. Med. 192, 813–821 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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).

    Article  CAS  PubMed  Google Scholar 

  94. Arce, S. et al. The role of long-lived plasma cells in autoimmunity. Immunobiology 206, 558–562 (2002).

    Article  PubMed  Google Scholar 

  95. Gorman, C., Leandro, M. & Isenberg, D. B cell depletion in autoimmune disease. Arthritis Res. Ther. 5 (Suppl. 4), S17–S21 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Hoyer, B. F. et al. Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J. Exp. Med. 199, 1577–1584 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Takahashi, Y., Dutta, P. R., Cerasoli, D. M. & Kelsoe, G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. V. Affinity maturation develops in two stages of clonal selection. J. Exp. Med. 187, 885–895 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kunkel, E. J. & Butcher, E. C. Plasma-cell homing. Nature Rev. Immunol. 3, 822–829 (2003).

    Article  CAS  Google Scholar 

  99. Hargreaves, D. C. et al. A coordinated change in chemokine responsiveness guides plasma cell movements. J. Exp. Med. 194, 45–56 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hopken, U. E., Achtman, A. H., Kruger, K. & Lipp, M. Distinct and overlapping roles of CXCR5 and CCR7 in B-1 cell homing and early immunity against bacterial pathogens. J. Leukoc. Biol. 76, 709–718 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Hauser, A. E. et al. Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune response. J. Immunol. 169, 1277–1282 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Odendahl, M. et al. Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response. Blood 105, 1614–1621 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Underhill, G. H. et al. IgG plasma cells display a unique spectrum of leukocyte adhesion and homing molecules. Blood 99, 2905–2912 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Manz, R. A. & Radbruch, A. Plasma cells for a lifetime? Eur. J. Immunol. 32, 923–927 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Ellyard, J. I. et al. Antigen-selected, immunoglobulin-secreting cells persist in human spleen and bone marrow. Blood 103, 3805–3812 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Minges Wols, H. A., Underhill, G. H., Kansas, G. S. & Witte, P. L. The role of bone marrow-derived stromal cells in the maintenance of plasma cell longevity. J. Immunol. 169, 4213–4221 (2002). In this study, isolating normal plasma cells and culturing them in vitro showed that stromal cells provide survival signals to plasma cells. The plasma cells stimulate the stromal cells to produce IL-6, a crucial survival factor.

    Article  CAS  PubMed  Google Scholar 

  107. O'Connor, B. P. et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med. 199, 91–98 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Cassese, G. et al. Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals. J. Immunol. 171, 1684–1690 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Cortes, M. & Georgopoulos, K. Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity. J. Exp. Med. 199, 209–219 (2004). Analysis of mice deficient in Aiolos showed that long-lived plasma cells did not appear in the bone marrow, establishing a requirement for Aiolos in this process.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Lee, A. H., Iwakoshi, N. N., Anderson, K. C. & Glimcher, L. H. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc. Natl Acad. Sci. USA 100, 9946–9951 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ren, B., Chee, K. J., Kim, T. H. & Maniatis, T. PRDI-BF1/Blimp-1 repression is mediated by corepressors of the Groucho family of proteins. Genes Dev. 13, 125–137 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Gyory, I., Wu, J., Fejer, G., Seto, E. & Wright, K. L. PRDI-BF1 recruits the histone H3 methyltransferase G9a in transcriptional silencing. Nature Immunol. 5, 299–308 (2004).

    Article  CAS  Google Scholar 

  114. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Berland, R. & Wortis, H. H. Origins and functions of B-1 cells with notes on the role of CD5. Annu. Rev. Immunol. 20, 253–300 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Rothstein, T. L. Two B-1 or not to be one. J. Immunol. 168, 4257–4261 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Wardemann, H., Boehm, T., Dear, N. & Carsetti, R. B-1a B cells that link the innate and adaptive immune responses are lacking in the absence of the spleen. J. Exp. Med. 195, 771–780 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bikah, G., Carey, J., Ciallella, J. R., Tarakhovsky, A. & Bondada, S. CD5-mediated negative regulation of antigen receptor-induced growth signals in B-1 B cells. Science 274, 1906–1909 (1996).

    Article  CAS  PubMed  Google Scholar 

  119. Hippen, K. L., Tze, L. E. & Behrens, T. W. CD5 maintains tolerance in anergic B cells. J. Exp. Med. 191, 883–890 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Berland, R. & Wortis, H. H. Normal B-1a cell development requires B cell-intrinsic NFATc1 activity. Proc. Natl Acad. Sci. USA 100, 13459–13464 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Karras, J. G. et al. Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in normal, self-renewing B-1 cells but only inducibly expressed in conventional B lymphocytes. J. Exp. Med. 185, 1035–1042 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ye, B. H. et al. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science 262, 747–750 (1993).

    Article  CAS  PubMed  Google Scholar 

  123. Chang, C. C., Ye, B. H., Chaganti, R. S. & Dalla-Favera, R. BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor. Proc. Natl Acad. Sci. USA 93, 6947–6952 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Keller, A. D. & Maniatis, T. Identification and characterization of a novel repressor of β-interferon gene expression. Genes Dev. 5, 868–879 (1991).

    Article  CAS  PubMed  Google Scholar 

  125. Kuo, T. C. & Calame, K. L. B lymphocyte-induced maturation protein (Blimp)-1, IFN regulatory factor (IRF)-1, and IRF-2 can bind to the same regulatory sites. J. Immunol. 173, 5556–5563 (2004).

    Article  CAS  PubMed  Google Scholar 

  126. Marecki, S. & Fenton, M. J. The role of IRF-4 in transcriptional regulation. J. Interferon Cytokine Res. 22, 121–133 (2002).

    Article  CAS  PubMed  Google Scholar 

  127. Hemesath, T. J. et al. Microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family. Genes Dev. 8, 2770–2780 (1994).

    Article  CAS  PubMed  Google Scholar 

  128. Fujita, N. et al. MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell 113, 207–219 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Adams, B. et al. Pax-5 encodes the transcription factor BSAP and is expressed in B lymphocytes, the developing CNS, and adult testis. Genes Dev. 6, 1589–1607 (1992).

    Article  CAS  PubMed  Google Scholar 

  130. Liou, H. C. et al. A new member of the leucine zipper class of proteins that binds to the HLA DR α promoter. Science 247, 1581–1584 (1990).

    Article  CAS  PubMed  Google Scholar 

  131. Shapiro-Shelef, M. & Calame, K. Regulation of normal and malignant plasma cells. Curr. Opin. Immunol. 16, 226–230 (2004).

    Article  CAS  PubMed  Google Scholar 

  132. Messika, E. et al. Differential effect of Blimp-1 expression on cell fate during B cell development. J. Exp. Med. 188, 515–525 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Departments of Microbiology, and Biochemistry and Molecular Biophysics, Columbia University College of Physicians and Surgeons, New York, 10032, New York, USA

    Miriam Shapiro-Shelef & Kathryn Calame

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  1. Miriam Shapiro-Shelef
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Correspondence to Kathryn Calame.

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DATABASES

Entrez Gene

BACH2

BCL-6

BLIMP1

IRF4

MITF

MTA3

PAX5

XBP1

Glossary

μM

The transmembrane form of the μ immunoglobulin heavy chain. μS denotes the alternative form, which is secreted.

PLASMA CELLS

Non-dividing, terminally differentiated, immunoglobulin-secreting cells of the B-cell lineage.

MARGINAL ZONE

A region at the border of the white pulp of the spleen.

T-CELL-INDEPENDENT TYPE 2 ANTIGENS

(TI-2 antigens). Antigens that contain multiple identical epitopes, which crosslink B-cell receptors.

SOMATICALLY MUTATED

Immunoglobulin genes that have undergone somatic hypermutation (SHM). SHM is a unique mutation mechanism that is targeted to the variable regions of rearranged immunoglobulin gene segments. Combined with selection for B cells that produce high-affinity antibody, SHM leads to affinity maturation of B cells in the germinal centre.

ANTIBODY-SECRETING CELLS

(ASCs). Denotes both proliferating plasmablasts and non-proliferating plasma cells. The term is used when both cell types might be present.

CLASS-SWITCH RECOMBINATION

(CSR). A DNA rearrangement in which deletion replaces one immunoglobulin heavy-chain constant-region gene segment (usually μ) with a more 3′ gene segment (γ, ε or α).

FOLLICULAR DENDRITIC CELLS

(FDCs). Specialized cells of unknown origin, which hold antigen–antibody complexes in germinal centres and are crucial for optimal selection of B cells that produce antigen-binding antibody.

CPG-CONTAINING OLIGODEOXYNUCLEOTIDES

DNA oligonucleotides that contain unmethylated CpG bases, which are commonly found in bacteria.

ACTIVATION-INDUCED CYTIDINE DEAMINASE

(AID). An enzyme that is required for two crucial events in the germinal centre: somatic hypermutation and class-switch recombination.

SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION

(STAT). Member of a family of transcription factors that is activated in response to cytokines.

TOLL-LIKE RECEPTOR

(TLR). Member of a family of receptors that is homologous to Drosophila melanogaster Toll. TLRs recognize different molecular patterns that are present in pathogens.

INOSITOL-REQUIRING 1α

(IRE1α). An integral membrane protein that is resident in the endoplasmic reticulum and has kinase and endoribonuclease activity. It is activated in the unfolded-protein response and processes mRNA that encodes X-box-binding protein 1 (XBP1).

ACTIVATING TRANSCRIPTION FACTOR 6

(ATF6). A basic leucine-zipper transcription factor that, when activated by cleavage, initiates expression of genes that are involved in the unfolded-protein response.

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Shapiro-Shelef, M., Calame, K. Regulation of plasma-cell development. Nat Rev Immunol 5, 230–242 (2005). https://doi.org/10.1038/nri1572

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