Immunologic Research

, Volume 55, Issue 1–3, pp 231–240 | Cite as

Antigen and cytokine receptor signals guide the development of the naïve mature B cell repertoire

  • Sarah L. Rowland
  • Kathryn Tuttle
  • Raul M. Torres
  • Roberta Pelanda
Immunology in Colorado


Immature B cells are generated daily in the bone marrow tissue. More than half of the newly generated immature B cells are autoreactive and bind a self-antigen, while the others are nonautoreactive. A selection process has evolved on the one hand to thwart development of autoreactive immature B cells and, on the other hand, to promote further differentiation of nonautoreactive immature B cells into transitional and mature B cells. These negative and positive selection events are carefully regulated by signals that emanate from the antigen receptor, whether antigen-mediated or tonic, and are influenced by signals that are generated by receptors that bind cytokines, chemokines, and other factors produced in the bone marrow tissue. These signals, therefore, are the predominant driving forces for the generation of a B cell population that is capable of protecting the body from infections while maintaining self-tolerance. Here, we review recent findings from our group and others that describe how tonic antigen receptor signaling and bone marrow cytokines regulate the selection of immature B cells.


B cell development B cell selection B cell tolerance Bone marrow BCR signaling Cytokine 



We thank present and past members of our laboratories who have contributed to the work and discussions presented here. Work in the authors’ laboratory was and/or is supported by the National Institutes of Health grants AI022295, AI052310, AI052157, AI078468, the Arthritis Foundation and a Cancer Research Institute Pre-Doctoral training grant.


  1. 1.
    Hardy RR, Carmack CE, Shinton SA, Kemp JD, Hayakawa K. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J Exp Med. 1991;173(5):1213–25.PubMedCrossRefGoogle Scholar
  2. 2.
    Pelanda R, Schaal S, Torres RM, Rajewsky K. A prematurely expressed Ig(kappa) transgene, but not V(kappa)J(kappa) gene segment targeted into the Ig(kappa) locus, can rescue B cell development in lambda5-deficient mice. Immunity. 1996;5(3):229–39.PubMedCrossRefGoogle Scholar
  3. 3.
    Grandien A, Fucs R, Nobrega A, Andersson J, Coutinho A. Negative selection of multireactive B cell clones in normal adult mice. Eur J Immunol. 1994;24(6):1345–52.PubMedCrossRefGoogle Scholar
  4. 4.
    Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. Predominant autoantibody production by early human B cell precursors. Science. 2003;301(5638):1374–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Nemazee D. Receptor selection in B and T lymphocytes. Annu Rev Immunol. 2000;18:19–51.PubMedCrossRefGoogle Scholar
  6. 6.
    Goodnow CC, Sprent J, Fazekas de St Groth B, Vinuesa CG. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature. 2005;435(7042):590–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Pelanda R, Torres RM. Receptor editing for better or for worse. Curr Opin Immunol. 2006;18(2):184–90.PubMedCrossRefGoogle Scholar
  8. 8.
    Shlomchik MJ. Sites and stages of autoreactive B cell activation and regulation. Immunity. 2008;28(1):18–28.PubMedCrossRefGoogle Scholar
  9. 9.
    Yarkoni Y, Getahun A, Cambier JC. Molecular underpinning of B-cell anergy. Immunol Rev. 2010;237(1):249–63.PubMedCrossRefGoogle Scholar
  10. 10.
    Loder F, Mutschler B, Ray RJ, Paige CJ, Sideras P, Torres R, et al. B cell development in the spleen takes place in discrete steps and is determined by the quality of B cell receptor-derived signals. J Exp Med. 1999;190(1):75–89.PubMedCrossRefGoogle Scholar
  11. 11.
    Allman D, Lindsley RC, DeMuth W, Rudd K, Shinton SA, Hardy RR. Resolution of three nonproliferative immature splenic B cell subsets reveals multiple selection points during peripheral B cell maturation. J Immunol. 2001;167(12):6834–40.PubMedGoogle Scholar
  12. 12.
    Su TT, Rawlings DJ. Transitional B lymphocyte subsets operate as distinct checkpoints in murine splenic B cell development. J Immunol. 2002;168(5):2101–10.PubMedGoogle Scholar
  13. 13.
    Tarlinton D, Light A, Metcalf D, Harvey RP, Robb L. Architectural defects in the spleens of Nk2–3-deficient mice are intrinsic and associated with defects in both B cell maturation and T cell-dependent immune responses. J Immunol. 2003;170(8):4002–10.PubMedGoogle Scholar
  14. 14.
    Reichman-Fried M, Hardy RR, Bosma MJ. Development of B-lineage cells in the bone marrow of scid/scid mice following the introduction of functionally rearranged immunoglobulin transgenes. Proc Natl Acad Sci USA. 1990;87(7):2730–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Spanopoulou E, Roman CA, Corcoran LM, Schlissel MS, Silver DP, Nemazee D, et al. Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice. Genes Dev. 1994;8(9):1030–42.PubMedCrossRefGoogle Scholar
  16. 16.
    Young F, Ardman B, Shinkai Y, Lansford R, Blackwell TK, Mendelsohn M, et al. Influence of immunoglobulin heavy- and light-chain expression on B-cell differentiation. Genes Dev. 1994;8(9):1043–57.PubMedCrossRefGoogle Scholar
  17. 17.
    Torres RM, Flaswinkel H, Reth M, Rajewsky K. Aberrant B cell development and immune response in mice with a compromised BCR complex. Science. 1996;272(5269):1804–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Tze LE, Schram BR, Lam KP, Hogquist KA, Hippen KL, Liu J, et al. Basal immunoglobulin signaling actively maintains developmental stage in immature B cells. PLoS Biol. 2005;3(3):e82.PubMedCrossRefGoogle Scholar
  19. 19.
    Meffre E, Nussenzweig MC. Deletion of immunoglobulin beta in developing B cells leads to cell death. Proc Natl Acad Sci USA. 2002;99(17):11334–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Kraus M, Alimzhanov MB, Rajewsky N, Rajewsky K. Survival of resting mature B lymphocytes depends on BCR signaling via the Igalpha/beta heterodimer. Cell. 2004;117(6):787–800.PubMedCrossRefGoogle Scholar
  21. 21.
    Bannish G, Fuentes-Panana EM, Cambier JC, Pear WS, Monroe JG. Ligand-independent signaling functions for the B lymphocyte antigen receptor and their role in positive selection during B lymphopoiesis. J Exp Med. 2001;194(11):1583–96.PubMedCrossRefGoogle Scholar
  22. 22.
    Monroe JG. Ligand-independent tonic signaling in B-cell receptor function. Curr Opin Immunol. 2004;16(3):288–95.PubMedCrossRefGoogle Scholar
  23. 23.
    D’Apuzzo M, Rolink A, Loetscher M, Hoxie JA, Clark-Lewis I, Melchers F, et al. The chemokine SDF-1, stromal cell-derived factor 1, attracts early stage B cell precursors via the chemokine receptor CXCR4. Eur J Immunol. 1997;27(7):1788–93.PubMedCrossRefGoogle Scholar
  24. 24.
    Marshall AJ, Fleming HE, Wu GE, Paige CJ. Modulation of the IL-7 dose-response threshold during pro-B cell differentiation is dependent on pre-B cell receptor expression. J Immunol. 1998;161(11):6038–45.PubMedGoogle Scholar
  25. 25.
    Ma Q, Jones D, Springer TA. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity. 1999;10(4):463–71.PubMedCrossRefGoogle Scholar
  26. 26.
    Zhang Y, Lu L, Furlonger C, Wu GE, Paige CJ. Hemokinin is a hematopoietic-specific tachykinin that regulates B lymphopoiesis. Nat Immunol. 2000;1(5):392–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Tokoyoda K, Egawa T, Sugiyama T, Choi BI, Nagasawa T. Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity. 2004;20(6):707–18.PubMedCrossRefGoogle Scholar
  28. 28.
    Pereira JP, An J, Xu Y, Huang Y, Cyster JG. Cannabinoid receptor 2 mediates the retention of immature B cells in bone marrow sinusoids. Nat Immunol. 2009;10(4):403–11.PubMedCrossRefGoogle Scholar
  29. 29.
    Milne CD, Paige CJ. IL-7: a key regulator of B lymphopoiesis. Semin Immunol. 2006;18(1):20–30.PubMedCrossRefGoogle Scholar
  30. 30.
    Lam KP, Kuhn R, Rajewsky K. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell. 1997;90(6):1073–83.PubMedCrossRefGoogle Scholar
  31. 31.
    Srinivasan L, Sasaki Y, Calado DP, Zhang B, Paik JH, DePinho RA, et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell. 2009;139(3):573–86.PubMedCrossRefGoogle Scholar
  32. 32.
    Rosado MM, Freitas AA. The role of the B cell receptor V region in peripheral B cell survival. Eur J Immunol. 1998;28(9):2685–93.PubMedCrossRefGoogle Scholar
  33. 33.
    Verkoczy L, Duong B, Skog P, Ait-Azzouzene D, Puri K, Vela JL, et al. Basal B cell receptor-directed phosphatidylinositol 3-kinase signaling turns off RAGs and promotes B cell-positive selection. J Immunol. 2007;178(10):6332–41.PubMedGoogle Scholar
  34. 34.
    Schram BR, Tze LE, Ramsey LB, Liu J, Najera L, Vegoe AL, et al. B cell receptor basal signaling regulates antigen-induced Ig light chain rearrangements. J Immunol. 2008;180(7):4728–41.PubMedGoogle Scholar
  35. 35.
    Verkoczy L, Ait-Azzouzene D, Skog P, Martensson A, Lang J, Duong B, et al. A role for nuclear factor kappa B/rel transcription factors in the regulation of the recombinase activator genes. Immunity. 2005;22(4):519–31.PubMedCrossRefGoogle Scholar
  36. 36.
    Pelanda R, Hobeika E, Kurokawa T, Zhang Y, Kuppig S, Reth M. Cre recombinase-controlled expression of the mb-1 allele. Genesis. 2002;32(2):154–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Rowland SL, DePersis CL, Torres RM, Pelanda R. Ras activation of Erk restores impaired tonic BCR signaling and rescues immature B cell differentiation. J Exp Med. 2010;207(3):607–21.PubMedCrossRefGoogle Scholar
  38. 38.
    Melamed D, Benschop RJ, Cambier JC, Nemazee D. Developmental regulation of B lymphocyte immune tolerance compartmentalizes clonal selection from receptor selection. Cell. 1998;92(2):173–82.PubMedCrossRefGoogle Scholar
  39. 39.
    Healy JI, Goodnow CC. Positive versus negative signaling by lymphocyte antigen receptors. Annu Rev Immunol. 1998;16:645–70.PubMedCrossRefGoogle Scholar
  40. 40.
    Gauld SB, Dal Porto JM, Cambier JC. B cell antigen receptor signaling: roles in cell development and disease. Science. 2002;296(5573):1641–2.PubMedCrossRefGoogle Scholar
  41. 41.
    Werner M, Hobeika E, Jumaa H. Role of PI3K in the generation and survival of B cells. Immunol Rev. 2010;237(1):55–71.PubMedCrossRefGoogle Scholar
  42. 42.
    Li Y, Li H, Weigert M. Autoreactive B cells in the marginal zone that express dual receptors. J Exp Med. 2002;195(2):181–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Liu S, Velez MG, Humann J, Rowland S, Conrad FJ, Halverson R, et al. Receptor editing can lead to allelic inclusion and development of B cells that retain antibodies reacting with high avidity autoantigens. J Immunol. 2005;175(8):5067–76.PubMedGoogle Scholar
  44. 44.
    Huang H, Kearney JF, Grusby MJ, Benoist C, Mathis D. Induction of tolerance in arthritogenic B cells with receptors of differing affinity for self-antigen. Proc Natl Acad Sci USA. 2006;103(10):3734–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Casellas R, Zhang Q, Zheng NY, Mathias MD, Smith K, Wilson PC. Igkappa allelic inclusion is a consequence of receptor editing. J Exp Med. 2007;204(1):153–60.PubMedCrossRefGoogle Scholar
  46. 46.
    Velez MG, Kane M, Liu S, Gauld SB, Cambier JC, Torres RM, et al. Ig allotypic inclusion does not prevent B cell development or response. J Immunol. 2007;179(2):1049–57.PubMedGoogle Scholar
  47. 47.
    Monroe JG. ITAM-mediated tonic signalling through pre-BCR and BCR complexes. Nat Rev Immunol. 2006;6(4):283–94.PubMedCrossRefGoogle Scholar
  48. 48.
    Yang J, Reth M. Oligomeric organization of the B-cell antigen receptor on resting cells. Nature. 2010;467(7314):465–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Omerovic J, Laude AJ, Prior IA. Ras proteins: paradigms for compartmentalised and isoform-specific signalling. Cell Mol Life Sci. 2007;64(19–20):2575–89.PubMedCrossRefGoogle Scholar
  50. 50.
    Gibbs JB, Sigal IS, Poe M, Scolnick EM. Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules. Proc Natl Acad Sci USA. 1984;81(18):5704–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 1989;49(17):4682–9.PubMedGoogle Scholar
  52. 52.
    Krishna M, Narang H. The complexity of mitogen-activated protein kinases (MAPKs) made simple. Cell Mol Life Sci. 2008;65(22):3525–44.PubMedCrossRefGoogle Scholar
  53. 53.
    Alberola-Ila J, Hernandez-Hoyos G. The Ras/MAPK cascade and the control of positive selection. Immunol Rev. 2003;191:79–96.PubMedCrossRefGoogle Scholar
  54. 54.
    Iritani BM, Forbush KA, Farrar MA, Perlmutter RM. Control of B cell development by Ras-mediated activation of Raf. EMBO J. 1997;16(23):7019–31.PubMedCrossRefGoogle Scholar
  55. 55.
    Yasuda T, Sanjo H, Pages G, Kawano Y, Karasuyama H, Pouyssegur J, et al. Erk kinases link pre-B cell receptor signaling to transcriptional events required for early B cell expansion. Immunity. 2008;28(4):499–508.PubMedCrossRefGoogle Scholar
  56. 56.
    Alberola-Ila J, Hogquist KA, Swan KA, Bevan MJ, Perlmutter RM. Positive and negative selection invoke distinct signaling pathways. J Exp Med. 1996;184(1):9–18.PubMedCrossRefGoogle Scholar
  57. 57.
    Werlen G, Hausmann B, Palmer E. A motif in the alphabeta T-cell receptor controls positive selection by modulating ERK activity. Nature. 2000;406(6794):422–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Fischer AM, Katayama CD, Pages G, Pouyssegur J, Hedrick SM. The role of erk1 and erk2 in multiple stages of T cell development. Immunity. 2005;23(4):431–43.PubMedCrossRefGoogle Scholar
  59. 59.
    McNeil LK, Starr TK, Hogquist KA. A requirement for sustained ERK signaling during thymocyte positive selection in vivo. Proc Natl Acad Sci USA. 2005;102(38):13574–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Schilling M, Maiwald T, Hengl S, Winter D, Kreutz C, Kolch W, et al. Theoretical and experimental analysis links isoform-specific ERK signalling to cell fate decisions. Mol Syst Biol. 2009;5:334.PubMedCrossRefGoogle Scholar
  61. 61.
    Diamant E, Keren Z, Melamed D. CD19 regulates positive selection and maturation in B lymphopoiesis: lack of CD19 imposes developmental arrest of immature B cells and consequential stimulation of receptor editing. Blood. 2005;105(8):3247–54.PubMedCrossRefGoogle Scholar
  62. 62.
    Wienands J, Larbolette O, Reth M. Evidence for a preformed transducer complex organized by the B cell antigen receptor. Proc Natl Acad Sci USA. 1996;93(15):7865–70.PubMedCrossRefGoogle Scholar
  63. 63.
    Shaw AC, Swat W, Ferrini R, Davidson L, Alt FW. Activated Ras signals developmental progression of recombinase-activating gene (RAG)-deficient pro-B lymphocytes. J Exp Med. 1999;189(1):123–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Rowland SL, Leahy KF, Halverson R, Torres RM, Pelanda R. BAFF receptor signaling aids the differentiation of immature B cells into transitional B cells following tonic BCR signaling. J Immunol. 2010;185(8):4570–81.PubMedCrossRefGoogle Scholar
  65. 65.
    Ferrell JE Jr, Machleder EM. The biochemical basis of an all-or-none cell fate switch in Xenopus oocytes. Science. 1998;280(5365):895–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Daniels MA, Teixeiro E, Gill J, Hausmann B, Roubaty D, Holmberg K, et al. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature. 2006;444(7120):724–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Das J, Ho M, Zikherman J, Govern C, Yang M, Weiss A, et al. Digital signaling and hysteresis characterize Ras activation in lymphoid cells. Cell. 2009;136(2):337–51.PubMedCrossRefGoogle Scholar
  68. 68.
    Otipoby KL, Sasaki Y, Schmidt-Supprian M, Patke A, Gareus R, Pasparakis M, et al. BAFF activates Akt and Erk through BAFF-R in an IKK1-dependent manner in primary mouse B cells. Proc Natl Acad Sci USA. 2008;105(34):12435–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Rodriguez-Viciana P, Sabatier C, McCormick F. Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Mol Cell Biol. 2004;24(11):4943–54.PubMedCrossRefGoogle Scholar
  70. 70.
    Liu K, Liang C, Liang Z, Tus K, Wakeland EK. Sle1ab mediates the aberrant activation of STAT3 and Ras-ERK signaling pathways in B lymphocytes. J Immunol. 2005;174(3):1630–7.PubMedGoogle Scholar
  71. 71.
    Kumar KR, Li L, Yan M, Bhaskarabhatla M, Mobley AB, Nguyen C, et al. Regulation of B cell tolerance by the lupus susceptibility gene Ly108. Science. 2006;312(5780):1665–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Hartley SB, Cooke MP, Fulcher DA, Harris AW, Cory S, Basten A, et al. Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death. Cell. 1993;72(3):325–35.PubMedCrossRefGoogle Scholar
  73. 73.
    Melamed D, Nemazee D. Self-antigen does not accelerate immature B cell apoptosis, but stimulates receptor editing as a consequence of developmental arrest. Proc Natl Acad Sci USA. 1997;94(17):9267–72.PubMedCrossRefGoogle Scholar
  74. 74.
    Casellas R, Shih TA, Kleinewietfeld M, Rakonjac J, Nemazee D, Rajewsky K, et al. Contribution of receptor editing to the antibody repertoire. Science. 2001;291(5508):1541–4.PubMedCrossRefGoogle Scholar
  75. 75.
    Halverson R, Torres RM, Pelanda R. Receptor editing is the main mechanism of B cell tolerance toward membrane antigens. Nat Immunol. 2004;5(6):645–50.PubMedCrossRefGoogle Scholar
  76. 76.
    Witte PL, Frantsve LM, Hergott M, Rahbe SM. Cytokine production and heterogeneity of primary stromal cells that support B lymphopoiesis. Eur J Immunol. 1993;23(8):1809–17.PubMedCrossRefGoogle Scholar
  77. 77.
    Funk PE, Stephan RP, Witte PL. Vascular cell adhesion molecule 1-positive reticular cells express interleukin-7 and stem cell factor in the bone marrow. Blood. 1995;86(7):2661–71.PubMedGoogle Scholar
  78. 78.
    Wei C, Zeff R, Goldschneider I. Murine pro-B cells require IL-7 and its receptor complex to up-regulate IL-7R alpha, terminal deoxynucleotidyltransferase, and c mu expression. J Immunol. 2000;164(4):1961–70.PubMedGoogle Scholar
  79. 79.
    Pelanda R, Schwers S, Sonoda E, Torres RM, Nemazee D, Rajewsky K. Receptor editing in a transgenic mouse model: site, efficiency, and role in B cell tolerance and antibody diversification. Immunity. 1997;7(6):765–75.PubMedCrossRefGoogle Scholar
  80. 80.
    Ait-Azzouzene D, Verkoczy L, Peters J, Gavin A, Skog P, Vela JL, et al. An immunoglobulin C kappa-reactive single chain antibody fusion protein induces tolerance through receptor editing in a normal polyclonal immune system. J Exp Med. 2005;201(5):817–28.PubMedCrossRefGoogle Scholar
  81. 81.
    Hippen KL, Schram BR, Tze LE, Pape KA, Jenkins MK, Behrens TW. In vivo assessment of the relative contributions of deletion, anergy, and editing to B cell self-tolerance. J Immunol. 2005;175(2):909–16.PubMedGoogle Scholar
  82. 82.
    Milne CD, Fleming HE, Paige CJ. IL-7 does not prevent pro-B/pre-B cell maturation to the immature/sIgM(+) stage. Eur J Immunol. 2004;34(10):2647–55.PubMedCrossRefGoogle Scholar
  83. 83.
    Lentz VM, Cancro MP, Nashold FE, Hayes CE. Bcmd governs recruitment of new B cells into the stable peripheral B cell pool in the A/WySnJ mouse. J Immunol. 1996;157(2):598–606.PubMedGoogle Scholar
  84. 84.
    Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science. 1999;285(5425):260–3.PubMedCrossRefGoogle Scholar
  85. 85.
    Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999;189(11):1747–56.PubMedCrossRefGoogle Scholar
  86. 86.
    Thompson JS, Schneider P, Kalled SL, Wang L, Lefevre EA, Cachero TG, et al. BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population. J Exp Med. 2000;192(1):129–35.PubMedCrossRefGoogle Scholar
  87. 87.
    Gross JA, Dillon SR, Mudri S, Johnston J, Littau A, Roque R, et al. TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. Impaired B cell maturation in mice lacking BLyS. Immunity. 2001;15(2):289–302.PubMedCrossRefGoogle Scholar
  88. 88.
    Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles M, et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science. 2001;293(5537):2111–4.PubMedCrossRefGoogle Scholar
  89. 89.
    Yan M, Brady JR, Chan B, Lee WP, Hsu B, Harless S, et al. Identification of a novel receptor for B lymphocyte stimulator that is mutated in a mouse strain with severe B cell deficiency. Curr Biol. 2001;11(19):1547–52.PubMedCrossRefGoogle Scholar
  90. 90.
    Gorelik L, Cutler AH, Thill G, Miklasz SD, Shea DE, Ambrose C, et al. Cutting edge: BAFF regulates CD21/35 and CD23 expression independent of its B cell survival function. J Immunol. 2004;172(2):762–6.PubMedGoogle Scholar
  91. 91.
    Sasaki Y, Casola S, Kutok JL, Rajewsky K, Schmidt-Supprian M. TNF family member B cell-activating factor (BAFF) receptor-dependent and -independent roles for BAFF in B cell physiology. J Immunol. 2004;173(4):2245–52.PubMedGoogle Scholar
  92. 92.
    Hsu BL, Harless SM, Lindsley RC, Hilbert DM, Cancro MP. Cutting edge: BLyS enables survival of transitional and mature B cells through distinct mediators. J Immunol. 2002;168(12):5993–6.PubMedGoogle Scholar
  93. 93.
    Tussiwand R, Rauch M, Fluck LA, Rolink AG. BAFF-R expression correlates with positive selection of immature B cells. Eur J Immunol. 2012;42(1):206–16.PubMedCrossRefGoogle Scholar
  94. 94.
    Claudio E, Saret S, Wang H, Siebenlist U. Cell-autonomous role for NF-kappa B in immature bone marrow B cells. J Immunol. 2009;182(6):3406–13.PubMedCrossRefGoogle Scholar
  95. 95.
    Giltiay NV, Lu Y, Allman D, Jorgensen TN, Li X. The adaptor molecule Act1 regulates BAFF responsiveness and self-reactive B cell selection during transitional B cell maturation. J Immunol. 2010;185(1):99–109.PubMedCrossRefGoogle Scholar
  96. 96.
    Vosshenrich CA, Cumano A, Muller W, Di Santo JP, Vieira P. Pre-B cell receptor expression is necessary for thymic stromal lymphopoietin responsiveness in the bone marrow but not in the liver environment. Proc Natl Acad Sci USA. 2004;101(30):11070–5.PubMedCrossRefGoogle Scholar
  97. 97.
    Benson MJ, Dillon SR, Castigli E, Geha RS, Xu S, Lam KP, et al. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J Immunol. 2008;180(6):3655–9.PubMedGoogle Scholar
  98. 98.
    Sapoznikov A, Pewzner-Jung Y, Kalchenko V, Krauthgamer R, Shachar I, Jung S. Perivascular clusters of dendritic cells provide critical survival signals to B cells in bone marrow niches. Nat Immunol. 2008;9(4):388–95.PubMedCrossRefGoogle Scholar
  99. 99.
    Yeramilli VA, Knight KL. Requirement for BAFF and APRIL during B cell development in GALT. J Immunol. 2010;184(10):5527–36.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Sarah L. Rowland
    • 1
  • Kathryn Tuttle
    • 1
  • Raul M. Torres
    • 1
  • Roberta Pelanda
    • 1
  1. 1.Integrated Department of ImmunologyUniversity of Colorado School of Medicine, National Jewish HealthDenverUSA

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