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Control systems and decision making for antibody production

Nature Immunology volume 11, pages 681–688 (2010)Cite this article

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Abstract

This paper synthesizes recent progress toward understanding the integrated control systems and fail-safes that guide the quality and quantity of antibody produced by B cells. We focus on four key decisions: (1) the choice between proliferation or death in perifollicular B cells in the first 3 days after antigen encounter; (2) differentiation of proliferating perifollicular B cells into extrafollicular plasma cells or germinal center B cells; (3) positive selection of B cell antigen receptor (BCR) affinity for foreign antigen versus negative selection of BCR affinity for self antigen in germinal center B cells; and (4) survival versus death of antibody-secreting plasma cells. Understanding the engineering of these control systems represents a challenging future step for treating disorders of antibody production in autoimmunity, allergy and immunodeficiency.

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Figure 1: Key B cell decisions after antigen exposure.
Figure 2: Proposed mechanism for concurrent positive and negative affinity selection of GC B cells.

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References

  1. Ehrlich, P. On immunity with special reference to cell life. Proc. Roy. Soc. Lond. 66, 424–448 (1900).

    Article  CAS  Google Scholar 

  2. Burnet, F.M. The Clonal Selection Theory of Acquired Immunity (Cambridge Univ. Press, Cambridge, UK, 1959).

  3. Lederberg, J. Genes and antibodies. Science 129, 1649–1653 (1959).

    CAS  PubMed  Google Scholar 

  4. Goodnow, C.C., Sprent, J., de St. Groth, B.F. & Vinuesa, C.G. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature 435, 590–597 (2005).

    CAS  PubMed  Google Scholar 

  5. Bretscher, P. & Cohn, M. A theory of self-nonself discrimination: paralysis and induction involve the recognition of one and two determinants on an antigen, respectively. Science 169, 1042–1049 (1970).

    CAS  PubMed  Google Scholar 

  6. Elgueta, R. et al. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol. Rev. 229, 152–172 (2009).

    CAS  PubMed  Google Scholar 

  7. Moller, G. One non-specific signal triggers B lymphocytes. Transplant. Rev. 23, 126–137 (1975).

    CAS  PubMed  Google Scholar 

  8. Cyster, J.G. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu. Rev. Immunol. 23, 127–159 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Glynne, R. et al. How self-tolerance and the immunosuppressive drug FK506 prevent B-cell mitogenesis. Nature 403, 672–676 (2000).

    CAS  PubMed  Google Scholar 

  10. Liu, Y.-J., Zhang, J., Lane, P.J.L., Chan, E.Y.-T. & MacLennan, I.C.M. Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens. Eur. J. Immunol. 21, 2951–2962 (1991).

    CAS  PubMed  Google Scholar 

  11. Reif, K. et al. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 416, 94–99 (2002).

    PubMed  Google Scholar 

  12. Okada, T. et al. Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. PLoS Biol. 3, e150 (2005).

    PubMed  PubMed Central  Google Scholar 

  13. Rathmell, J.C., Fournier, S., Weintraub, B.C., Allison, J.P. & Goodnow, C.C. Repression of B7.2 on self-reactive B cells is essential to prevent proliferation and allow Fas-mediated deletion by CD4+ T cells. J. Exp. Med. 188, 651–659 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Rathmell, J.C., Townsend, S.E., Xu, J.C., Flavell, R.A. & Goodnow, C.C. Expansion or elimination of B cells in vivo: dual roles for CD40- and Fas (CD95)-ligands modulated by the B cell antigen receptor. Cell 87, 319–329 (1996).

    CAS  PubMed  Google Scholar 

  15. Cyster, J.G., Hartley, S.B. & Goodnow, C.C. Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire. Nature 371, 389–395 (1994).

    CAS  PubMed  Google Scholar 

  16. Cyster, J.G. & Goodnow, C.C. Antigen-induced exclusion from follicles and anergy are separate and complementary processes that influence peripheral B cell fate. Immunity 3, 691–701 (1995).

    CAS  PubMed  Google Scholar 

  17. Ekland, E.H., Forster, R., Lipp, M. & Cyster, J.G. Requirements for follicular exclusion and competitive elimination of autoantigen-binding B cells. J. Immunol. 172, 4700–4708 (2004).

    CAS  PubMed  Google Scholar 

  18. Chan, T.D. et al. Antigen affinity controls rapid T-dependent antibody production by driving the expansion rather than the differentiation or extrafollicular migration of early plasmablasts. J. Immunol. 183, 3139–3149 (2009).

    CAS  PubMed  Google Scholar 

  19. Coffey, F., Alabyev, B. & Manser, T. Initial clonal expansion of germinal center B cells takes place at the perimeter of follicles. Immunity 30, 599–609 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Steinman, R.M., Pack, M. & Inaba, K. Dendritic cells in the T-cell areas of lymphoid organs. Immunol. Rev. 156, 25–37 (1997).

    CAS  PubMed  Google Scholar 

  21. MacLennan, I.C. et al. Extrafollicular antibody responses. Immunol. Rev. 194, 8–18 (2003).

    CAS  PubMed  Google Scholar 

  22. Bergtold, A., Desai, D.D., Gavhane, A. & Clynes, R. Cell surface recycling of internalized antigen permits dendritic cell priming of B cells. Immunity 23, 503–514 (2005).

    CAS  PubMed  Google Scholar 

  23. Qi, H., Egen, J.G., Huang, A.Y. & Germain, R.N. Extrafollicular activation of lymph node B cells by antigen-bearing dendritic cells. Science 312, 1672–1676 (2006).

    CAS  PubMed  Google Scholar 

  24. Turner, M.L., Hawkins, E.D. & Hodgkin, P.D. Quantitative regulation of B cell division destiny by signal strength. J. Immunol. 181, 374–382 (2008).

    CAS  PubMed  Google Scholar 

  25. Hawkins, E.D., Markham, J.F., McGuinness, L.P. & Hodgkin, P.D. A single-cell pedigree analysis of alternative stochastic lymphocyte fates. Proc. Natl. Acad. Sci. USA 106, 13457–13462 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Pereira, J.P., Kelly, L.M., Xu, Y. & Cyster, J.G. EBI2 mediates B cell segregation between the outer and centre follicle. Nature 460, 1122–1126 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Gatto, D., Paus, D., Basten, A., Mackay, C.R. & Brink, R. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses. Immunity 31, 259–269 (2009).

    CAS  PubMed  Google Scholar 

  28. Jacob, J. & Kelsoe, G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. II. A common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers. J. Exp. Med. 176, 679–687 (1992).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 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).

    CAS  PubMed  Google Scholar 

  31. Shaffer, A.L. et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13, 199–212 (2000).

    CAS  PubMed  Google Scholar 

  32. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Shapiro-Shelef, M. & Calame, K. Regulation of plasma-cell development. Nat. Rev. Immunol. 5, 230–242 (2005).

    CAS  PubMed  Google Scholar 

  34. Sciammas, R. et al. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25, 225–236 (2006).

    CAS  PubMed  Google Scholar 

  35. Klein, U. et al. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat. Immunol. 7, 773–782 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Saito, M. et al. A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell 12, 280–292 (2007).

    CAS  PubMed  Google Scholar 

  37. 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).

    CAS  PubMed  Google Scholar 

  38. Tangye, S.G., Avery, D.T. & Hodgkin, P.D. A division-linked mechanism for the rapid generation of Ig-secreting cells from human memory B cells. J. Immunol. 170, 261–269 (2003).

    CAS  PubMed  Google Scholar 

  39. 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. Nat. Immunol. 5, 55–63 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. 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).

    CAS  PubMed  Google Scholar 

  41. Avery, D.T. et al. B cell–intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J. Exp Med 207, 155–171 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Rui, L., Vinuesa, C.G., Blasioli, J. & Goodnow, C.C. Resistance to CpG DNA–induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling. Nat. Immunol. 4, 594–600 (2003).

    PubMed  Google Scholar 

  43. Kwakkenbos, M.J. et al. Generation of stable monoclonal antibody–producing B cell receptor–positive human memory B cells by genetic programming. Nat. Med. 16, 123–128 (2010).

    CAS  PubMed  Google Scholar 

  44. Kusam, S., Vasanwala, F.H. & Dent, A.L. Transcriptional repressor BCL-6 immortalizes germinal center-like B cells in the absence of p53 function. Oncogene 23, 839–844 (2004).

    CAS  PubMed  Google Scholar 

  45. Takahashi, Y. et al. Relaxed negative selection in germinal centers and impaired affinity maturation in bcl-xL transgenic mice. J. Exp. Med. 190, 399–410 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Cunningham, A.F. et al. Salmonella induces a switched antibody response without germinal centers that impedes the extracellular spread of infection. J. Immunol. 178, 6200–6207 (2007).

    CAS  PubMed  Google Scholar 

  47. Eckl-Dorna, J. & Batista, F.D. BCR-mediated uptake of antigen linked to TLR9 ligand stimulates B-cell proliferation and antigen-specific plasma cell formation. Blood 113, 3969–3977 (2009).

    CAS  PubMed  Google Scholar 

  48. Ma, C.S., Nichols, K.E. & Tangye, S.G. Regulation of cellular and humoral immune responses by the SLAM and SAP families of molecules. Annu. Rev. Immunol. 25, 337–379 (2007).

    CAS  PubMed  Google Scholar 

  49. 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).

    CAS  PubMed  Google Scholar 

  50. Qi, H., Cannons, J.L., Klauschen, F., Schwartzberg, P.L. & Germain, R.N. SAP-controlled T–B cell interactions underlie germinal centre formation. Nature 455, 764–769 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Linterman, M.A. et al. Follicular helper T cells are required for systemic autoimmunity. J. Exp. Med. 206, 561–576 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Cannons, J.L. et al. Optimal germinal center responses require a multistage T cell:B cell adhesion process involving integrins, SLAM-associated protein, and CD84. Immunity 32, 253–265 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Vinuesa, C.G., Tangye, S.G., Moser, B. & Mackay, C.R. Follicular B helper T cells in antibody responses and autoimmunity. Nat. Rev. Immunol. 5, 853–865 (2005).

    CAS  PubMed  Google Scholar 

  54. Yu, D. et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31, 457–468 (2009).

    CAS  PubMed  Google Scholar 

  55. Johnston, R.J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006–1010 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Nurieva, R.I. et al. Bcl6 mediates the development of T follicular helper cells. Science 325, 1001–1005 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Ozaki, K. et al. A critical role for IL-21 in regulating immunoglobulin production. Science 298, 1630–1634 (2002).

    CAS  PubMed  Google Scholar 

  58. Vogelzang, A. et al. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29, 127–137 (2008).

    CAS  PubMed  Google Scholar 

  59. Linterman, M.A. et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J. Exp. Med. 207, 353–363 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Zotos, D. et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J. Exp. Med. 207, 365–378 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Shih, T.A., Meffre, E., Roederer, M. & Nussenzweig, M.C. Role of BCR affinity in T cell dependent antibody responses in vivo. Nat. Immunol. 3, 570–575 (2002).

    PubMed  Google Scholar 

  62. Anderson, S.M. et al. Taking advantage: high-affinity B cells in the germinal center have lower death rates, but similar rates of division, compared to low-affinity cells. J. Immunol. 183, 7314–7325 (2009).

    CAS  PubMed  Google Scholar 

  63. Martin, S.W. & Goodnow, C.C. Burst-enhancing role of the IgG membrane tail as a molecular determinant of memory. Nat. Immunol. 3, 182–188 (2002).

    CAS  PubMed  Google Scholar 

  64. Radic, M.Z. & Weigert, M. Genetic and structural evidence for antigen selection of anti-DNA antibodies. Annu. Rev. Immunol. 12, 487–520 (1994).

    CAS  PubMed  Google Scholar 

  65. Goodnow, C.C. & Basten, A. Self-tolerance in B lymphocytes. Sem. Immunol. 1, 125–135 (1989).

    CAS  Google Scholar 

  66. Nossal, G.J., Ada, G.L. & Austin, C.M. Behaviour of active bacterial antigens during the induction of the immune response. II. Cellular distribution of flagellar antigens labelled with iodine-131. Nature 199, 1259–1262 (1963).

    CAS  PubMed  Google Scholar 

  67. Carroll, M.C. The role of complement and complement receptors in induction and regulation of immunity. Annu. Rev. Immunol. 16, 545–568 (1998).

    CAS  PubMed  Google Scholar 

  68. Nossal, G.J., Ada, G.L., Austin, C.M. & Pye, J. Antigens in immunity. 8. Localization of 125-I-labelled antigens in the secondary response. Immunology 9, 349–357 (1965).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. El Shikh, M.E., El Sayed, R., Szakal, A.K. & Tew, J.G. Follicular dendritic cell (FDC)-FcγRIIB engagement via immune complexes induces the activated FDC phenotype associated with secondary follicle development. Eur. J. Immunol. 36, 2715–2724 (2006).

    CAS  PubMed  Google Scholar 

  70. Phan, T.G., Gray, E.E. & Cyster, J.G. The microanatomy of B cell activation. Curr. Opin. Immunol. 21, 258–265 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Shokat, K.M. & Goodnow, C.C. Antigen-induced B-cell death and elimination during germinal-centre immune responses. Nature 375, 334–338 (1995).

    CAS  PubMed  Google Scholar 

  72. Pulendran, B., Kannourakis, G., Nouri, S., Smith, K.G. & Nossal, G.J. Soluble antigen can cause enhanced apoptosis of germinal-centre B cells. Nature 375, 331–334 (1995).

    CAS  PubMed  Google Scholar 

  73. Han, S., Zheng, B., Dal Porto, J. & Kelsoe, G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. IV. Affinity-dependent, antigen-driven B cell apoptosis in germinal centers as a mechanism for maintaining self-tolerance. J. Exp. Med. 182, 1635–1644 (1995).

    CAS  PubMed  Google Scholar 

  74. Alabyev, B., Rahman, Z.S. & Manser, T. Quantitatively reduced participation of anti-nuclear antigen B cells that down-regulate B cell receptor during primary development in the germinal center/memory B cell response to foreign antigen. J. Immunol. 178, 5623–5634 (2007).

    CAS  PubMed  Google Scholar 

  75. Fleire, S.J. et al. B cell ligand discrimination through a spreading and contraction response. Science 312, 738–741 (2006).

    CAS  PubMed  Google Scholar 

  76. Allen, C.D., Okada, T., Tang, H.L. & Cyster, J.G. Imaging of germinal center selection events during affinity maturation. Science 315, 528–531 (2007).

    CAS  PubMed  Google Scholar 

  77. Han, S. et al. Cellular interaction in germinal centers: roles of CD40 ligand and B7–2 in established germinal centers. J. Immunol. 155, 556–567 (1995).

    CAS  PubMed  Google Scholar 

  78. Vinuesa, C.G. et al. A novel RING-type ubiquitin ligase family member essential to repress follicular helper T cells and autoimmunity. Nature 435, 452–458 (2005).

    CAS  PubMed  Google Scholar 

  79. Huntington, N.D. et al. CD45 links the B cell receptor with cell survival and is required for the persistence of germinal centers. Nat. Immunol. 7, 190–198 (2006).

    CAS  PubMed  Google Scholar 

  80. Tuveson, D.A., Carter, R.H., Soltoff, S.P. & Fearon, D.T. CD19 of B cells as a surrogate kinase insert region to bind phosphatidylinositol 3-kinase. Science 260, 986–989 (1993).

    CAS  PubMed  Google Scholar 

  81. Rickert, R.C., Rajewsky, K. & Roes, J. Impairment of T-cell-dependent B cell responses and B-1 cell development in CD19-deficient mice. Nature 376, 352–355 (1995).

    CAS  PubMed  Google Scholar 

  82. Engel, P. et al. Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Immunity 3, 39–50 (1995).

    CAS  PubMed  Google Scholar 

  83. Wang, Y. & Carter, R.H. CD19 regulates B cell maturation, proliferation, and positive selection in the FDC zone of murine splenic germinal centers. Immunity 22, 749–761 (2005).

    CAS  PubMed  Google Scholar 

  84. van Zelm, M.C. et al. An antibody-deficiency syndrome due to mutations in the CD19 gene. N. Engl. J. Med. 354, 1901–1912 (2006).

    CAS  PubMed  Google Scholar 

  85. Anzelon, A.N., Wu, H. & Rickert, R.C. Pten inactivation alters peripheral B lymphocyte fate and reconstitutes CD19 function. Nat. Immunol. 4, 287–294 (2003).

    CAS  PubMed  Google Scholar 

  86. Clayton, E. et al. A crucial role for the p110δ subunit of phosphatidylinositol 3-kinase in B cell development and activation. J. Exp. Med. 196, 753–763 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Okkenhaug, K. et al. Impaired B and T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice. Science 297, 1031–1034 (2002).

    CAS  PubMed  Google Scholar 

  88. Jou, S.T. et al. Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the B-cell receptor complex. Mol. Cell. Biol. 22, 8580–8591 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Okkenhaug, K., Ali, K. & Vanhaesebroeck, B. Antigen receptor signalling: a distinctive role for the p110δ isoform of PI3K. Trends Immunol. 28, 80–87 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Fruman, D.A. Phosphoinositide 3-kinase and its targets in B-cell and T-cell signaling. Curr. Opin. Immunol. 16, 314–320 (2004).

    CAS  PubMed  Google Scholar 

  91. Cote, J.F. & Vuori, K. GEF what? Dock180 and related proteins help Rac to polarize cells in new ways. Trends Cell Biol. 17, 383–393 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Randall, K.L. et al. Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production. Nat. Immunol. 10, 1283–1291 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Zhang, Q. et al. Combined immunodeficiency associated with DOCK8 mutations. N. Engl. J. Med. 361, 2046–2055 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Engelhardt, K.R. et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J. Allergy Clin. Immunol. 124, 1289–1302 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Arana, E. et al. Activation of the small GTPase Rac2 via the B cell receptor regulates B cell adhesion and immunological-synapse formation. Immunity 28, 88–99 (2008).

    CAS  PubMed  Google Scholar 

  96. Depoil, D. et al. CD19 is essential for B cell activation by promoting B cell receptor–antigen microcluster formation in response to membrane-bound ligand. Nat. Immunol. 9, 63–72 (2008).

    CAS  PubMed  Google Scholar 

  97. Giancotti, F.G. & Ruoslahti, E. Integrin signaling. Science 285, 1028–1032 (1999).

    CAS  PubMed  Google Scholar 

  98. Buchner, M. et al. Spleen tyrosine kinase inhibition prevents chemokine- and integrin-mediated stromal protective effects in chronic lymphocytic leukemia. Blood 115, 4497–4506 (2010).

    CAS  PubMed  Google Scholar 

  99. Costello, P.S., Gallagher, M. & Cantrell, D.A. Sustained and dynamic inositol lipid metabolism inside and outside the immunological synapse. Nat. Immunol. 3, 1082–1089 (2002).

    CAS  PubMed  Google Scholar 

  100. Huppa, J.B., Gleimer, M., Sumen, C. & Davis, M.M. Continuous T cell receptor signaling required for synapse maintenance and full effector potential. Nat. Immunol. 4, 749–755 (2003).

    CAS  PubMed  Google Scholar 

  101. Victoratos, P. et al. FDC-specific functions of p55TNFR and IKK2 in the development of FDC networks and of antibody responses. Immunity 24, 65–77 (2006).

    CAS  PubMed  Google Scholar 

  102. Koopman, G. et al. Adhesion through the LFA-1 (CD11a/CD18)-ICAM-1 (CD54) and the VLA-4 (CD49d)-VCAM-1 (CD106) pathways prevents apoptosis of germinal center B cells. J. Immunol. 152, 3760–3767 (1994).

    CAS  PubMed  Google Scholar 

  103. Manning, B.D. & Cantley, L.C. AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Krajewski, S. et al. Immunohistochemical analysis of Mcl-1 and Bcl-2 proteins in normal and neoplastic lymph nodes. Am. J. Pathol. 145, 515–525 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Hartley, S.B. et al. Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death. Cell 72, 325–335 (1993).

    CAS  PubMed  Google Scholar 

  106. Srinivasan, L. et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell 139, 573–586 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Verkoczy, L. et al. Basal B cell receptor-directed phosphatidylinositol 3-kinase signaling turns off RAGs and promotes B cell-positive selection. J. Immunol. 178, 6332–6341 (2007).

    CAS  PubMed  Google Scholar 

  108. Tze, L.E. et al. Basal immunoglobulin signaling actively maintains developmental stage in immature B cells. PLoS Biol. 3, e82 (2005).

    PubMed  PubMed Central  Google Scholar 

  109. Amin, R.H. & Schlissel, M.S. Foxo1 directly regulates the transcription of recombination-activating genes during B cell development. Nat. Immunol. 9, 613–622 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Herzog, S. et al. SLP-65 regulates immunoglobulin light chain gene recombination through the PI(3)K-PKB-Foxo pathway. Nat. Immunol. 9, 623–631 (2008).

    CAS  PubMed  Google Scholar 

  111. Mackay, F. & Schneider, P. Cracking the BAFF code. Nat. Rev. Immunol. 9, 491–502 (2009).

    CAS  PubMed  Google Scholar 

  112. Smith, K.G. et al. bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody-forming cells. J. Exp. Med. 191, 475–484 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Smith, K.G., Light, A., Nossal, G.J. & Tarlinton, D.M. The extent of affinity maturation differs between the memory and antibody-forming cell compartments in the primary immune response. EMBO J. 16, 2996–3006 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Phan, T.G. et al. High affinity germinal center B cells are actively selected into the plasma cell compartment. J. Exp. Med. 203, 2419–2424 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 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).

    CAS  PubMed  Google Scholar 

  116. DiLillo, D.J. et al. Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice. J. Immunol. 180, 361–371 (2008).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  118. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Garcia De Vinuesa, C. et al. Dendritic cells associated with plasmablast survival. Eur. J. Immunol. 29, 3712–3721 (1999).

    CAS  PubMed  Google Scholar 

  120. Ng, L.G. et al. BAFF-R is the principal BAFF receptor facilitating BAFF co-stimulation of B and T cells. J. Immunol. 173, 807–817 (2004).

    CAS  PubMed  Google Scholar 

  121. Darce, J.R., Arendt, B.K., Wu, X. & Jelinek, D.F. Regulated expression of BAFF-binding receptors during human B cell differentiation. J. Immunol. 179, 7276–7286 (2007).

    CAS  PubMed  Google Scholar 

  122. Avery, D.T. et al. BAFF selectively enhances the survival of plasmablasts generated from human memory cells. J. Clin. Invest. 112, 286–297 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Bossen, C. et al. TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts. Blood 111, 1004–1012 (2008).

    CAS  PubMed  Google Scholar 

  124. O'Connor, B.P. et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med. 199, 91–97 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Benson, M.J. et al. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J. Immunol. 180, 3655–3659 (2008).

    CAS  PubMed  Google Scholar 

  126. Ramanujam, M. et al. Similarities and differences between selective and nonselective BAFF blockade in murine SLE. J. Clin. Invest. 116, 724–734 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Belnoue, E. et al. APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells. Blood 111, 2755–2764 (2008).

    CAS  PubMed  Google Scholar 

  128. Huard, B. et al. BAFF production by antigen-presenting cells provides T cell co-stimulation. Int. Immunol. 16, 467–475 (2004).

    CAS  PubMed  Google Scholar 

  129. Scholz, J.L. et al. BLyS inhibition eliminates primary B cells but leaves natural and acquired humoral immunity intact. Proc. Natl. Acad. Sci. USA 105, 15517–15522 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Gatto, B. Atacicept, a homodimeric fusion protein for the potential treatment of diseases triggered by plasma cells. Curr. Opin. Investig. Drugs 9, 1216–1227 (2008).

    CAS  PubMed  Google Scholar 

  131. Cassese, G. et al. Inflamed kidneys of NZB/W mice are a major site for the homeostasis of plasma cells. Eur. J. Immunol. 31, 2726–2732 (2001).

    CAS  PubMed  Google Scholar 

  132. Withers, D.R. et al. T cell-dependent survival of CD20+ and CD20− plasma cells in human secondary lymphoid tissue. Blood 109, 4856–4864 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank our collaborators and colleagues for input. Supported by the Australian National Health and Medical Research Council, Australian Research Council, Wellcome Trust and US National Institutes of Health's National Institute of Allergy and Infectious Diseases.

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Authors and Affiliations

  1. John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.,

    Christopher C Goodnow, Carola G Vinuesa & Katrina L Randall

  2. Department of Immunology, The Canberra Hospital, Garran, Australian Capital Territory, Australia.,

    Katrina L Randall

  3. Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia

    Fabienne Mackay

  4. Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

    Robert Brink

  5. St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia

    Robert Brink

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  1. Christopher C Goodnow
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  2. Carola G Vinuesa
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Correspondence to Christopher C Goodnow.

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Goodnow, C., Vinuesa, C., Randall, K. et al. Control systems and decision making for antibody production. Nat Immunol 11, 681–688 (2010). https://doi.org/10.1038/ni.1900

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