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CD 19 function in central and peripheral B-cell development

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Abstract

Although the B-cell antigen receptor (BCR) factors most prominently in the maintenance and differentiation of mature B cells, it is now appreciated that co-receptor molecules can positively or negatively modulate signals through the BCR. Co-receptors are functionally defined as modifiers of BCR engagement and signal transuction, and are distinct from other accessory molecules that act independently to regulate B-cell growth. The co-receptor CD19 functions to augment signals by the pre-BCR/BCR and in doing so can modulate B-cell fate decisions at multiple stages of development. In mature B cells, CD 19 also associates with complement receptor 2 (CR2/CD21) and is privotal for transducing signals inducdd by co-recognition of complement C3d-fixed antigens by the BCR and CD21. In this article, we focus on recent progress in the understanding of CD 19 function through the characterization of mouse models that relate in vivo function to biochemical properties of CD 19.

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References

  1. Tedder, TF, Isaacs CM: Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily. J Immunol 1989;143:712.

    PubMed  CAS  Google Scholar 

  2. Bradbury LE, Goldmacher VS, Tedder TF: The CD19 signal transduction complex of B lymphocytes. Deletion of the CD19 cytoplasmic domain alters signal transduction but not complex formation with TAPA-1 and Leu 13. J Immunol 1993; 151:2915.

    PubMed  CAS  Google Scholar 

  3. Matsumoto AK, Martin DR, Carter RH, et al.: Functional dissection of the CD 21/CD19/TAPA-1/Leu-13 complex of B lymphocytes. J Exp Med 1993;178:1407.

    Article  PubMed  CAS  Google Scholar 

  4. Fearon DT, Carroll MC: Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Annu Rev Immunol 2000;18:393.

    Article  PubMed  CAS  Google Scholar 

  5. Carter RH, Fearon DT: CD19: Iowering the threshold for antigen receptor stimulation of B lymphocytes. Science 1992;256:105.

    Article  PubMed  CAS  Google Scholar 

  6. Dempsey PW, Allison ME, Akkaraju S, et al.: C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 1996;271:348.

    Article  PubMed  CAS  Google Scholar 

  7. Krop I, de Fougerolles AR, Hardy RR, et al.: Seltrenewal of B-1 lymphocytes is dependent on CD19. Eur J Immunol 1996;26:238.

    Article  PubMed  CAS  Google Scholar 

  8. Wolf ML, Weng WK, Stieglbauer KT, et al.: Functional effect of IL-7-enhanced CD 19 expression on human B cell precurfsors. J Immunol 1993;151:138.

    PubMed  CAS  Google Scholar 

  9. Krop I, Shaffer AL, Fearon DT, Schlissel MS: The signaling activity of murine CD 19 is regulated during cell development. J Immunol 1996;157:48.

    PubMed  CAS  Google Scholar 

  10. Otero DC, Rickert RC: CD 19 function in early and late B cell development. II. CD 19 facilitates the Pro-B/PreB transition. J Immunol 2003:171:5921.

    PubMed  CAS  Google Scholar 

  11. Billips LG, Nunez CA, Bertrand FER, et al.: Immunoglobulin recombinase gene activity is modulated reciprocally by in terleukin 7 and CD 19 in B cell progenitors. J Exp Med 1995;182:973.

    Article  PubMed  CAS  Google Scholar 

  12. Buhl AM, Nemazee D, Cambier JC, et al.: B-cell antigen receptor competence regulates B-lymphocyte selection and survival. Immunol Rev 2000:176:141.

    Article  PubMed  CAS  Google Scholar 

  13. Shivtiel S, Leider N, Sadeh O, et al: Impaired light chain allelic exclusion and lack of positive selection in immature B cells expressing incompetent receptor deficient of CD19. J Immunol 2002;168:5596.

    PubMed  CAS  Google Scholar 

  14. Engel, P, Zhou LJ, Ord DC, et al: Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD 19 signal transduction molecule. Immunity 1995;3:39.

    Article  PubMed  CAS  Google Scholar 

  15. Benschop RJ, Cambier JC: B cell development: signal transduction by antigen receptors and their surrogates. Curr Opin Immunol 1999;11:143.

    Article  PubMed  CAS  Google Scholar 

  16. Sato S, Steeber DA, Jansen PJ, Tedder TF: CD 19 expression levels regulate B lymphocyte development: human CD19 restores normal function in mice lacking endogenous CD 19 J Immunol 1997;158:4662.

    PubMed  CAS  Google Scholar 

  17. Nemazee DA, Bürki K: Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature 1989;337:562.

    Article  PubMed  CAS  Google Scholar 

  18. Goodnow CC, Crosbie J, Adelstein S, et al.: Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 1988;334:676.

    Article  PubMed  CAS  Google Scholar 

  19. Lavoie TB, Drohan WN, Smith-Gill SJ Experimental analysis by site-directed mutagenesis of somatic mutation effects on affinity and fine specificity in antibodies specific for lysozyme. J Immunol 1992:148:503.

    PubMed  CAS  Google Scholar 

  20. Prodeus AP, Goerg S, Shen LM, et al.: A critical role for complement in maintenance of self-tolerance. Immunity 1998;9:721.

    Article  PubMed  CAS  Google Scholar 

  21. Inaoki M, Sato S, Weintraub BC, Goodnow CC, Tedder TF, CD 19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes. J Exp Med 1997;186:1923.

    Article  PubMed  CAS  Google Scholar 

  22. Hasegawa M, Fujimoto M, Poe JC, et al.: CD19 can regulate B lymphocyte signal transduction independent of complement activation. J Immunol 2001;167:3190.

    PubMed  CAS  Google Scholar 

  23. Otero DC, Anzelon AN, Rickert RC: CD 19 function in early and late B cell development: I. Maintenance of follicular and marginal zone B cells requires CD 19-dependent survival signals. J Immunol 2003;170:73.

    PubMed  CAS  Google Scholar 

  24. 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 [see comments]. Cell 1997;90:1073.

    Article  PubMed  CAS  Google Scholar 

  25. Roberts T, Sow EC: Cutting edge: recruitment of the CD 19/CD21 coreceptor to B cell antigen receptor is required for antigen-mediated expression of B cl-2 by resting and cycling hen egg lysozyme transgenic B cells. J Immunol 1999;162:4377.

    PubMed  CAS  Google Scholar 

  26. Carter RH, Fearson DT: Polymeric C3dg primes human B lymphocytes for proliferation induced by anti-IgM. J Immunol 1989;143:1755.

    PubMed  CAS  Google Scholar 

  27. Rickert RC, Rajewsky K, Roes, J: Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice. Nature 1995;376:352.

    Article  PubMed  CAS  Google Scholar 

  28. Martin F, Kearney JF: Positive selection from newly formed to marginal zone B cells depends on the rate of clonal production, CD19, and btk. Immunity 2000; 12:39.

    Article  PubMed  CAS  Google Scholar 

  29. Wortis HH, Berland R: Cutting edge commentary: origins of B-1 cells. J Immunol 2001:166:2163.

    PubMed  CAS  Google Scholar 

  30. Martin F, Oliver AM, Kearney JF: Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 2001; 14:617.

    Article  PubMed  CAS  Google Scholar 

  31. Cariappa A, Tang M, Parng C, et al.: The follicular versus marginal zone B lymphocyte cell fate decision is regulated by Aiolos, Btk, and CD21. Immunity 2001;14:603.

    Article  PubMed  CAS  Google Scholar 

  32. Guinamard R, Okigaki M, Schlessinger J, Ravetch JV: Absence of marginal zone B cells in Pyk-2-deficient mice defines their role in the humoral response. Nat Immunol 2000;1:31.

    Article  PubMed  CAS  Google Scholar 

  33. Fukui Y, Hashimoto O, Sanui T, et al.: Haematopoietic cell-specific CDM family protein DOCK 2 is essential for lymphocyte migration. Nature 2001;412:826.

    Article  PubMed  CAS  Google Scholar 

  34. Girkontaite I, Missy K, Sakk V, et al.: Lsc is required for marginal zone B cells, regulation of lymphocyte motility and immune responses. Nat Immunol 2001;2:855.

    Article  PubMed  CAS  Google Scholar 

  35. Lu TT, Cyster JG: Integrin-medited long-term B cell retention in the splenic marginal zone. Science 2002; 297:409.

    Article  PubMed  CAS  Google Scholar 

  36. Chalupny NJ, Aruffo A, Esselstyn JM, et al.: Specific binding of Fyn and phosphatidylinositol 3-kinase to the B cell surface glycoprotein CD 19 through their src homology 2 domains. Eur J Immunol 1995;25:2987.

    Article  Google Scholar 

  37. Fehr T, Rickert RC, Odermatt B, et al.: Antiviral protection and germinal center formation, but impaired B cell memory in the absence of CD 19. J Exp Med 1998;188:145.

    Article  PubMed  CAS  Google Scholar 

  38. Liu YJ, Oldfield S, MacLennan IC: Memory B cells in T cell-dependent antibody responses colonize the splenic marginal zones. Eur J Immunol 1988;18:355.

    Article  PubMed  CAS  Google Scholar 

  39. Song H, Cerny J: Functional heterogeneity of marginal zone B cells revealed by their ability to generate both early antibody-forming cells and germinal centers with hypermutation and memory in response to a T-dependent antigen. J Exp Med 2003;198:1923.

    Article  PubMed  CAS  Google Scholar 

  40. Attanavanich K, Kearney JF: Marginal zone, but not follicular B cells, are potent activators of naive CD4 T cells. J Immunol 2004;172:803.

    PubMed  CAS  Google Scholar 

  41. Barrington R, Zhang M, Fischer M, Carroll MC: The role of complement in inflammation and adaptive immunity. Immunol Rev 2001;180:5.

    Article  PubMed  CAS  Google Scholar 

  42. Cherukuri A, Cheng PC, Pierce SK: The role of the CD19/CD21 complex in B cell processing and presentation of complement-tagged antigens. J Immunol 2001;167:163.

    PubMed  CAS  Google Scholar 

  43. Gardby E, Chen XJ, Lycke NY: Impaired CD40-signalling in CD19-deficient mice selectively affects Th2-dependent isotype switching. Scand J Immunol 2001;53:13.

    Article  PubMed  CAS  Google Scholar 

  44. Kawabe T, Naka T, Yoshida K, et al.: The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1994;1:167.

    Article  PubMed  CAS  Google Scholar 

  45. Randall TD, Heath AW, Santos-Argumedo L, et al.: Arrest of B lymphocyte terminal differentiation by CD40 signaling: mechanism for lack of antibody-secreting cells in germinal centers. Immunity 1998;8:733.

    Article  PubMed  CAS  Google Scholar 

  46. Han S, Hathcock K, Zheng B, et al.: Cellular interaction in germinal centers. Roles of CD40 ligand and B7-2 in established germinal centers. J Immunol 1995;155:556.

    PubMed  CAS  Google Scholar 

  47. Wang Y, Brooks SR, Li X, et al.: The physiologic role of CD19 cytoplasmic tyrosines. Immunity 2002;17:501.

    Article  PubMed  CAS  Google Scholar 

  48. Chalupny NJ, Kanner SB, Schieven GL, et al.: Tyrosine phosphorylation of CD19 in pre-B and mature B cells. Embo J 1993;12:2691.

    PubMed  CAS  Google Scholar 

  49. Fujimoto M, Fujimoto Y, Poe JC, et al.: CD19 regulates Src family protein tyrosine kinase activation in B lymphocytes through processive amplification. Immunity 2000;13:47.

    Article  PubMed  CAS  Google Scholar 

  50. Buhl AM, Cambier JC: Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase. J Immunol 1999;162:4438.

    PubMed  CAS  Google Scholar 

  51. Brooks SR, Li X, Volanakis EJ, Carter RH: Systematic analysis of the role of CD19 cytoplasmic tyrosines in enhancement of activation in Daudi human B cells: clustering of phospholipase C and Vav and of Grb2 and Sos with different CD19 tyrosines. J Immunol 2000; 164:3123.

    PubMed  CAS  Google Scholar 

  52. Tuveson DA, Carter RH, Soltoff SP, Fearon DT: CD19 of B cells as a surrogate kinase insert region to bind phosphatidylinositol 3-kinase. Science 1993;260:986.

    Article  PubMed  CAS  Google Scholar 

  53. van Noesel CJ, Lankester AC, van Schijndel GM, van Lier RA: The CR2/CD19 complex on human B cells contains the src-family kinase Lyn. Int Immunol 1993;5:699.

    Article  PubMed  Google Scholar 

  54. Xu Y, Beavitt S-JE, Harder KW, et al.: The activation and subsequent regulatory roles of Lyn and CD19 after B cell receptor ligation are independent. J Immunol 2002; 169:6910.

    PubMed  CAS  Google Scholar 

  55. Beitz LO, Fruman DA, Kurosaki T, et al.: SYK is upstream of phosphoinositide 3-kinase in B cell receptor signaling. J Biol Chem 1999;274:32662.

    Article  PubMed  CAS  Google Scholar 

  56. Yokozeki T, Adler K, Lankar D, Bonnerot C: B cell receptor-mediated Syk-independent activation of phosphatidylinositol 3-kinase, Ras, and mitogen-activated protein kinase pathways. J Immunol 2003;171:1328.

    PubMed  CAS  Google Scholar 

  57. Buhl AM, Pleiman CM, Rickert RC, Cambier JC: Qualitative regulation of B cell antigen receptor signaling by CD19: selective requirement for PI3-kinase activation, inositol-1,4,5-trisphosphate production and Ca2+ mobilization. J Exp Med 1997;186:1897.

    Article  PubMed  CAS  Google Scholar 

  58. Fujimoto M, Poe JC, Satterthwaite AB, et al.: Complementary roles for CD19 and Bruton's tyrosine kinase in B lymphocyte signal transduction. J Immunol 2002; 168:5465.

    PubMed  CAS  Google Scholar 

  59. Otero DC, Omori SA, Rickert RC: Cd19-dependent activation of Akt kinase in B-lymphocytes. J Biol Chem 2001;276:1474.

    Article  PubMed  CAS  Google Scholar 

  60. Kurosaki T: Regulation of B-cell signal transduction by adaptor proteins. Nature Rev Immunol 2002;2:354.

    Article  CAS  Google Scholar 

  61. Yamazaki T, Takeda K, Gotoh K, et al.: Essential immunoregulatory role for BCAP in B cell development and function. J Exp Med 2002;195:535.

    Article  PubMed  CAS  Google Scholar 

  62. Itoh S, Itoh M, Nishida K, et al.: Adapter molecule Grb2-associated binder 1 is specifically expressed in marginal zone B cells and negatively regulates thymus-independent antigen-2 responses. J Immunol 2002;168:5110.

    PubMed  CAS  Google Scholar 

  63. Clark MR, campbell KS, Kazlauskas A, et al.: The B cell antigen receptor complex: association of Ig-alpha and Ig-beta with distinct cytoplasmic effectors. Science 1992;258:123.

    Article  PubMed  CAS  Google Scholar 

  64. Lou ST, Carpino N, Takahashi Y, et al.: Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell Biol 2002;22:8580.

    Article  Google Scholar 

  65. Clayton E, Bardi G, Bell SE, et al.: A crucial role for the p110{delta} subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med 2002; 196:753.

    Article  PubMed  CAS  Google Scholar 

  66. Okkenhaug K, Bilancio A, Farjot G, et al.: Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 2002;297:1031.

    PubMed  CAS  Google Scholar 

  67. Fruman DA, Snapper SB, Yballe CM, et al.: Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha. Science 1999;283:393.

    Article  PubMed  CAS  Google Scholar 

  68. Fruman DA, Satterthwaite AB, Witte ON: Xid-like phenotypes: a B cell signalosome takes shape. Immunity 2000;13:1.

    Article  PubMed  CAS  Google Scholar 

  69. Suzuki H, Terauchi Y, Fujiwara M, et al.: 1999 Xid-like immunodeficiency in mice with disruption of the p85alpha subunit of phosphoinositide 3-kinase. Science 1999;283:390.

    Article  PubMed  CAS  Google Scholar 

  70. Anzelon AN, Wu H, Rickert RC: Pten inactivation alters peripheral B lymphocyte fate and reconstitutes CD19 function. Nat Immunol 2003;4:287.

    Article  PubMed  CAS  Google Scholar 

  71. Suzuki A, Kaisho T, Ohishi M, et al.: Critical roles of Pten in B cell homeostasis and immunglobulin class switch recombination. J Exp Med 2003;197:657.

    Article  PubMed  CAS  Google Scholar 

  72. Katan M, Allen VL: Modular PH and C2 domains in membrane attachment and other functions. FEBS Lett 1999;452:36.

    Article  PubMed  CAS  Google Scholar 

  73. Lawlor MA, Mora A, Ashby PR, et al.: Essential role of PDK1 in regulating cell size and development in mice. EMBO J 2002;21:3728.

    Article  PubMed  CAS  Google Scholar 

  74. Vanhaesebroeck B, Alessi DR: The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 346 Pt 2000;3:561.

    Google Scholar 

  75. O'Rourke LM, Tooze R, Turner M, et al.: CD19 as a membrane-anchored adaptor protein of B lymphocytes: costimulation of lipid and protein kinases by recuritment of Vav. Immunity 1998;8:635.

    Article  PubMed  Google Scholar 

  76. Rickert RC, Wloch MK, Hahn RL, Clarke SH: Binding analysis of antibodies produced by precursor and branch point intermediates of an anti-influenza hemag-glutinin B cell clone. Parallel replacement mutations do not confer increased avidity for hemagglutinin. J Immunol 1995;154:2209.

    PubMed  CAS  Google Scholar 

  77. Mills DM, Stolpa JC, Cambier JC: Cognate B cell signaling via MHC class II: Differential regulation of B cell antigen receptor and MHC class II/Ig-alphabeta signaling by CD22. J Immunol 2004;172:195.

    PubMed  CAS  Google Scholar 

  78. Yazawa N, Fujimoto M, Sato S, et al.: CD19 regulates innate immunity by the toll-like receptor RP105 signaling in B lymphocytes. Blood 2003.

  79. Hippen KL, Buhl AM, D'Ambrosio D, et al.: Fc gammaRIIB1 inhibition of BCR-mediated phosphoinositide hydrolysis and Ca2+ mobilization is integrated by CD19 dephosphorylation. Immunity 1997;7:49.

    Article  PubMed  CAS  Google Scholar 

  80. Kitanaka A, Ito C, Coustan-Smith E, Campana D: CD38 ligation in human B cell progenitors triggers tyrosine phosphorylation of CD19 and association of CD19 with lyn and phosphatidylinositol 3-kinase. J Immunol 1997; 159:184.

    PubMed  CAS  Google Scholar 

  81. Koncz G, Gergely J, Sarmay G: Fc gammaRIIb inhibits both B cell receptor-and CD19-induced Ca2+ mobilization in Fc gammaR-transfected human B cells. Int Immunol 1998;10:141.

    Article  PubMed  CAS  Google Scholar 

  82. Venkataraman C, Lu PJ, Buhl AM, et al.: CD72-mediated B cell activation involves recruitment of CD19 and activation of phosphatidylinositol 3-kinase. Eur J Immunol 1998;28:3003.

    Article  PubMed  CAS  Google Scholar 

  83. Bradbury LE, Kansas GS, Levy S, et al.: The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules. J Immunol 1992;149:2841.

    PubMed  CAS  Google Scholar 

  84. Kiener PA, Lioubin MN, Rohrschneider LR, et al.: Coligation of the antigen and Fc receptors gives rise to the selective modulation of intracellular signaling in B cells. Regulation of the association of phosphatidylinositol 3-kinase and inositol 5′-phosphatase with the antigen receptor complex. J Biol Chem 1997;272:3838.

    Article  PubMed  CAS  Google Scholar 

  85. Carter RH, Doody GM, Bolen JB, Fearon DT: Membrane IgM-induced tyrosine phosphorylation of CD19 requires a CD19 domain that mediates association with components of the B cell antigen receptor complex. J Immunol 1997;158:3062.

    PubMed  CAS  Google Scholar 

  86. Hayashi K, Yamamoto M, Nojima T, et al.: Distinct signaling requirements for Dmu selection, IgH allelic exclusion, pre-B cell transition, and tumor suppression in B cell progenitors. Immunity 2003;18:825.

    Article  PubMed  CAS  Google Scholar 

  87. Conley ME, Rohrer J, Rapalus L, et al.: Derects in early B-cell development: comparing the consequences of abnormalities in pre-BCR signaling in the human and the mouse. Immunol Rev 2000;178:75.

    Article  PubMed  CAS  Google Scholar 

  88. Toothaker LE, Henjes AJ, Weis JJ: Variability of CR2 gene products is due to alternative exon usage and different CR2 alleles. J Immunol 1989;142:3668.

    PubMed  CAS  Google Scholar 

  89. Molina H, Kinoshita T, Inoue K, et al.: A molecular and immunochemical characterization of mouse CR2. Evidence for a single gene model of mouse complement receptors 1 and 2. J Immunol 1990;145:2974.

    PubMed  CAS  Google Scholar 

  90. Barel M, Le Romancer M, Frade R: Activation of the EBV/C3d receptor (CR2, CD21) on human B lymphocyte surface triggers tyrosine phosphorylation of the 95-kDa nucleolin and its interaction with phosphatidylinositol 3 kinase. J Immunol 2001;166:3167.

    PubMed  CAS  Google Scholar 

  91. Cherukuri A, Cheng PC, Sohn HW, Pierce SK: The CD19/CD21 complex functions to prolong B cell antigen receptor signaling from lipid rafts. Immunity 2001;14:169.

    Article  PubMed  CAS  Google Scholar 

  92. Weng WK, Jarvis L, LeBien TW: Signaling through CD19 activates Vav/mitogen-activated protein kinase pathway and induces formation of a CD19/Vav/phosphatidylinositol 3-kinase complex in human B cell precursors. J Biol Chem 1994;269:32514.

    PubMed  CAS  Google Scholar 

  93. Zipfel PA, Grove M, Blackburn K, et al.: The c-Abl tyrosine kinase is regulated downstream of the B cell antigen receptor and interacts with CD19. J Immunol 2000;165:6872.

    PubMed  CAS  Google Scholar 

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Del Nagro, C.J., Otero, D.C., Anzelon, A.N. et al. CD 19 function in central and peripheral B-cell development. Immunol Res 31, 119–131 (2005). https://doi.org/10.1385/IR:31:2:119

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