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Positive and negative selection during B lymphocyte development

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Abstract

Our laboratory is interested in a variety of issues related to lymphocyte development. More specifically, we have focused on the processes that regulate the decision to commit to the B lymphocyte (B cell) lineage, then the subsequent signals that are involved in maintaining this commitment to the B cell lineage. These signals result in the positive selection of those B cells that properly execute the complex genetic changes associated with B cell development, then trigger the elimination of B cells that are responsive to self-antigens and, therefore, possess the potential to mediate autoimmune disease. Our general experimental approach has been to address these issues from the perspective of signal transduction. Our goal is to define the biochemical and genetic processes that are integrated in order to accomplish these selection processes. To do so, we employ in vivo animal models as well as more defined in vitro studies, using both primary and transformed cell lines. For the past several years, we have been primarily interested in the precise mechanisms by which the B cell antigen receptor (BCR), and intermediate forms of this receptor, regulate these complex developmental processes. We have used the ongoing studies described below as two representative examples of how we are approaching these issues and some of the insights that we have made. To place both of these studies in context, we will begin with a brief introduction into B cell development.

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References

  1. Coggeshall KM: Positive and negative signaling in B lymphocytes. Curr Top Microbiol Immunol 2000;245:213–260.

    PubMed  CAS  Google Scholar 

  2. Wienands J: The B-cell antigen receptor: formation of signaling complexes and the function of adaptor proteins. Curr Top Microbiol Immunol 2000;245:53–76.

    PubMed  CAS  Google Scholar 

  3. Hsueh RC, Scheuermann RH: Tyrosine kinase activation in the decision between growth, differentiation, and death responses initiated from the B cell antigen receptor. Adv Immunol 2000;75: 283–316.

    Article  PubMed  CAS  Google Scholar 

  4. Reth M, Wienands J, Schamel WW: An unsolved problem of the clonal selection theory and the model of anoligomeric B-cell antigen receptor. Immunol Rev 2000; 176:10–18.

    Article  PubMed  CAS  Google Scholar 

  5. Hardy RR, Carmack CE, Shinton SA, Kemp JD, Hayakawa K: Resolution and characterization of pro-B and pre-B cell stages in normal mouse bone marrow. J. Exp Med 1991;173:1213–1225.

    Article  PubMed  CAS  Google Scholar 

  6. Hardy RR, Hayakawa K: B cell development pathways. Annu Rev Immunol 2001;19:595–621.

    Article  PubMed  CAS  Google Scholar 

  7. Monroe JG: B-cell antigen receptor signaling in immature-stage B cells: integrating intrinsic and extrinsic signals. Curr Top Microbiol Immunol 2000;245:1–29.

    PubMed  CAS  Google Scholar 

  8. Osmond DG, Rolink A, Melchers F: Murine B lymphopoiesis: towards a unified model. Immunol Today 1998;19:65–68.

    Article  PubMed  CAS  Google Scholar 

  9. Martensson IL, Ceredig R: Review article: role of the surrogate light chain and the pre-B-cell receptor in mouse B-cell development. Immunology 2000;101:435–441.

    Article  PubMed  CAS  Google Scholar 

  10. Stoddart A, Fleming HE, Paige CJ: The role of the preBCR, the interleukin-7 receptor, and homotypic interactions during B-cell development. Immunol Rev 2000; 175:47–58.

    Article  PubMed  CAS  Google Scholar 

  11. Yankee TM, Clark EA: Signaling through the B cell antigen receptor in developing B cells. Rev Immunogenet 2000;2:185–203.

    PubMed  CAS  Google Scholar 

  12. Meffre E, Casellas R, Nussenzweig MC: Antibody regulation of B cell development. Nat Immunol 2000;1:379–385.

    Article  PubMed  CAS  Google Scholar 

  13. Tudor KS, Payne KJ, Yamashita Y, Kincade PW: Functional assessment of precursors from murine bone marrow suggests a sequence of early B lineage differentiation events. Immunity 2000;12:335–345.

    Article  PubMed  CAS  Google Scholar 

  14. Gong S, Nussenzweig MC: Regulation of an early developmental checkpoint in the B cell pathway by Ig beta. Science 1996;272:411–414.

    Article  PubMed  CAS  Google Scholar 

  15. Kitamura D, Roes J, Kuhn R, Rajewsky K: A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin muchain gene. Nature 1991;350:423–426.

    Article  PubMed  CAS  Google Scholar 

  16. Kitamura D, Kudo A, Schaal S, Muller W, Melchers F, Rajewsky K: A critical role of lambda 5 protein in B cell development. Cell 1992;69:823–831.

    Article  PubMed  CAS  Google Scholar 

  17. Mundt C, Licence S, Shimizu T, Melchers F, Martensson IL: Loss of precursor B cell expansion but not allelic exclusion in VpreB 1/Vpre B2 double-deficient mice. J Exp Med 2001;193:435–445.

    Article  PubMed  CAS  Google Scholar 

  18. Cheng AM, Rowley B, Pao W, Hayday A, Bolen JB, Pawson T: Syktyrosine kinase required for mouse viability and B-cell development. Nature 1995;378:303–306.

    Article  PubMed  CAS  Google Scholar 

  19. Jumaa H, Wollscheid B, Mitterer M, Wienands J, Reth M, Nielsen PJ: Abnormal development and function of B lymphocytes inmice deficient for the signaling adaptor protein SLP-65. Immunity 1999; 11:547–554.

    Article  PubMed  CAS  Google Scholar 

  20. Pappu R, Cheng AM, Li B, et al.: Requirement for B cell linker protein (BLNK) in B cell development. Science 1999;286:1949–1954.

    Article  PubMed  CAS  Google Scholar 

  21. Conley ME, Rohrer J, Rapalus L, Boylin EC, Minegishi Y: Defects in early B-cell development: comparing the consequences of abnormalities in pre-BCR signaling in the human and the mouse. Immunol Rev 2000;178:75–90.

    Article  PubMed  CAS  Google Scholar 

  22. Teh YM, Neuberger MS: The immunoglobulin (Ig)alpha and Igbet cytoplasmic domains are independently sufficient to signal B cell maturation and activation in transgenic mice. J Exp Med 1997;185:1753–1758.

    Article  PubMed  CAS  Google Scholar 

  23. Shaffer AL, Schlissel MS: A truncated heavy chain protein relieves the requirement for surrogate light chains in early B cell development. J Immunol 1997;159:1265–1275.

    PubMed  CAS  Google Scholar 

  24. Benschop RJ, Cambier JC: B cell development: signal transduction by antigen receptors and their surrogates. Curr Opin Immunol 1999; 11:143–151.

    Article  PubMed  CAS  Google Scholar 

  25. Neuberger MS: Antigen receptor signaling gives lymphocytes along life. Cell 1997;90:971–973.

    Article  PubMed  CAS  Google Scholar 

  26. Pillai S: The chosen few? Positive selection and the generation of naive B lymphocytes. Immunity 1999;10:493–502.

    Article  PubMed  CAS  Google Scholar 

  27. 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: 1073–1083.

    Article  PubMed  CAS  Google Scholar 

  28. Aoki Y, Isselbacher KJ, Cherayil BJ, Pillai S: Tyrosine phosphorylation of Blk and Fyn Src homology 2 domain-binding proteins occurs in response to antigen-receptor ligation in B cells and constitutively in pre-B cells. Proc Natl Acad Sci USA 1994;91: 4204–4208.

    Article  PubMed  CAS  Google Scholar 

  29. Matsuuchi L, Gold MR: New views of BCR structure and organization. Curr Opin Immunol 2001; 13:270–277.

    Article  PubMed  CAS  Google Scholar 

  30. Pleiman CM, Abrams C, Gauen LT, Bedzyk W, Jongstra J, Shaw AS, Cambier JC: Distinct p53/56 lyn and p59 fyn domains associate with nonphosphorylated and phosphorylated Ig-alpha. Proc Natl Acad Sci USA 1994;91:4268–4272.

    Article  PubMed  CAS  Google Scholar 

  31. Clark MR, Johnson SA, Cambier JC: Analysis of Ig-alpha-tyrosine kinase interaction reveals two levels of binding specificity and tyrosine phosphorylated Ig-alpha stimulation of Fynactivity. EMBO J 1994;13:1911–1919.

    PubMed  CAS  Google Scholar 

  32. Irving BA, Alt FW, Killeen N: Thymocyte development in the absence of pre-T cell receptorex tracellular immunoglobulin domains. Science 1998;280:905–908.

    Article  PubMed  CAS  Google Scholar 

  33. 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: 7865–7870.

    Article  PubMed  CAS  Google Scholar 

  34. Shaver A, Ng JB, Hall DA, Posner BI: The chemistry of peroxovanadium compounds relevant to insulin mimesis. Mol Cell Biochem 1995;153:5–15.

    Article  PubMed  CAS  Google Scholar 

  35. Smith KG, Fearon DT: Receptor modulators of B-cell receptor signalling—CD19/CD22. Curr Top Microbiol Immunol 2000;245: 195–212.

    PubMed  CAS  Google Scholar 

  36. Penninger JM, Irie-Sasaki J, Sasaki T, Oliveira-dos-Santos AJ: CD45: new jobs for an old acquaintance. Nat Immunol 2001;2:389–396.

    PubMed  CAS  Google Scholar 

  37. Tsubata T: Co-receptors on B lymphocytes. Curr Opin Immunol 1999;11:249–255.

    Article  PubMed  CAS  Google Scholar 

  38. Rosado MM, Freitas AA: The role of the B cell receptor V region in peripheral B cell survival. Eur J Immunol 1998;28:2685–2693.

    Article  PubMed  CAS  Google Scholar 

  39. Levine MH, Haberman AM, Sant'Angelo DB, Hannum LG, Cancro MP, Janeway CA, Shlomchik MJ: AB-cell receptor-specific selection step governs immature to mature B cell differentiation. Proc Natl Acad Sci USA 2000;97: 2743–2748.

    Article  PubMed  CAS  Google Scholar 

  40. Murali-Krishna K, Lau LL, Sambhara S, Lemonnier F, Altman J, Ahmed R: Persistence of memory CD8 T cells in MHC class I-deficient mice. Science 1999;286: 1377–1381.

    Article  PubMed  CAS  Google Scholar 

  41. Melchers F, Rolink A, Grawunder U, Winkler TH, Karasuyama H, Ghia P, Andersson J: Positive and negative selection events during B lymphopoiesis. Curr Opin Immunol 1995;7:214–227.

    Article  PubMed  CAS  Google Scholar 

  42. Rolink AG, Andersson J, Melchers F: Charaterization of immature B cells by a novel monoclonal antibody by turnover and by mitogen reactivity. Eur J Immunol 1998;28:3738–3748.

    Article  PubMed  CAS  Google Scholar 

  43. Carsetti R, Kohler G, Lamers MC: Transitional B cells are the target of negative selection in the B cell compartment. J Exp Med 1995; 181:2129–2140.

    Article  PubMed  CAS  Google Scholar 

  44. King LB, Sandel P, Sater RA, Monroe JG: Molecular mechanisms regulating negative selection in immature-stage B cells, in Monroe JG, Rotherberg EV (eds) Molecular Regulation of B and T Lymphocyte Development. Totowa, NJ, Humana, 1998.

    Google Scholar 

  45. Norvell A, Monroe JG: Acquisition of surface IgD fails to protect from tolerance-induction. Both surface IgM-and surface IgD-medaited signals induce apoptosis of immature murine B lymphocytes. J Immunol 1996;156:1328–1332.

    PubMed  CAS  Google Scholar 

  46. Norvell A, Mandik L, Monroe JG: Engagement of the antigen-receptor on immature murine B lymphocytes results in death by apoptosis. J Immunol 1995;154: 4404–4413.

    PubMed  CAS  Google Scholar 

  47. Monroe JG: Tolerance sensitivity of immature-stage B cells: can developmentally regulated B cell antigen receptor (BCR) signal transduction play a role? J Immunol 1996;156:2657–2660.

    PubMed  CAS  Google Scholar 

  48. Yellen AJ, Glenn W, Sukhatme VP, Cao X, Monroe JG: Signaling through surface IgM in tolerance-susceptible immature murine B lymphocytes. J Immunol 1991; 146:1446–1454.

    PubMed  CAS  Google Scholar 

  49. Sandel PC, Monroe JG: Negative selection of immature B cells by receptor editing ordeletion is determined by site of antigen encounter. Immunity 1999;10:289–299.

    Article  PubMed  CAS  Google Scholar 

  50. Carsetti R, Kohler G, Lamers MC: A role for immunoglobulin D: interference with tolerance induction. Eur J Immunol 1993;23: 168–178.

    Article  PubMed  CAS  Google Scholar 

  51. Brink R, Goodnow CC, Crosbie J, Adams E, Eris J, Mason DY, et al.: Immunoglobulin M and D antigen receptors are both capable of mediating B lymphocyte activation, deletion, or anergy after interaction with specific antigen. J Exp Med 1992;176:991–1005.

    Article  PubMed  CAS  Google Scholar 

  52. Roes J, Rajewsky K: Immunoglobulin D9kgD)-deficient mice reveal an auxgliary receptor function for IgD an antigen-mediated recruitment of B cells. J Exp Med 1993; 17:45–55.

    Article  Google Scholar 

  53. Nitschke L, Kosco MH, Kohler G, Lamers MC: Immunoglobulin D-deficient mice can mount normal immune responses to thymus-inderendent and-dependent antigens. Proc Natl Acad Sci USA 1993;90:1887–1891.

    Article  PubMed  CAS  Google Scholar 

  54. Carman JA, Wechsler-Reya RJ, Monroe JG: Immature stage B cells enter but do not progress beyond the early G1 phase of the cell cycle in response to antigen receptor signaling. J Immunol 1996;156: 4562–4569.

    PubMed  CAS  Google Scholar 

  55. Sater RA, Sandel PC, Monroe JG: BCR-induced apoptosis in primary transitional murine B cells: Signaling requirements and modulation by T cell help. Int Immunol 1998;10:1673–1682.

    Article  PubMed  CAS  Google Scholar 

  56. Tasker L, Marshall-Clarke S: Immature B cells from neonatal mice show a selective inability to up-regulate MHC class Ilex pression inresponse to antigen receptor ligation. Int Immunol 1997;9:475–484.

    Article  PubMed  CAS  Google Scholar 

  57. Benschop RJ, Melamed D, Nemazee D, Cambier JC: Distinct signal thresholds for the unique antigen receptor-linked gene expression programs in mature and immature B cells. J Exp Med 1999; 190:749–756.

    Article  PubMed  CAS  Google Scholar 

  58. King LB, Norvell A, Monroe JG: Antigen receptor-induced signal transduction im balances associated with the negative selection of immature B cellsl. J Immunol 1999;162:2655–2662.

    PubMed  CAS  Google Scholar 

  59. Choi HC, Kim J-H, Kinet J-P: Calcium mobilization viasphingosine kinase in signaling by the FcReRI antigen receptor. Nature 1996; 380:634–636.

    Article  PubMed  CAS  Google Scholar 

  60. Sadighi Akha AA, Willmott NJ, Brickley K, Dolphin AC, Galione A, Hunt SV: Anti-Ig induced calcium influx in rat B lymphocytes mediated by cGMP through a dihydropyridine-sensitive channel. J Biol Chem 1996;271:7297–7300.

    Article  PubMed  CAS  Google Scholar 

  61. Leitges M, Schmedt C, Guinamard R, Davoust J, Schall S, Stabel S, Tarakhovsky A: Immuno-deficiency in protein kinase Cβ-deficient mice. Science 1996;273: 788–791.

    Article  PubMed  CAS  Google Scholar 

  62. Allman DM, Ferguson SE, Cancro MP: Peripheral B cell maturation. I. Immature peripheral B cells in adults are heat-stable antigenhi and exhibit unique signaling characteristics. J Immunol 1992;149:2533–2540.

    PubMed  CAS  Google Scholar 

  63. Hartley SS, Crosbie J, Brink R, Kantor AB, Basten A, Goodnow CC: Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature 1991;353:765–769.

    Article  PubMed  CAS  Google Scholar 

  64. Chen C, et al: The site and stage of anti-DNA B-cell deletion. Nature 1995;373:252–255.

    Article  PubMed  CAS  Google Scholar 

  65. Nemazee D, Buerki K: Clonaldeletion of autoreactive B lymphocytes in bone marrow chimeras. Proc Natl Acad Sci USA 1989;86:8039–8043.

    Article  PubMed  CAS  Google Scholar 

  66. Tiegs SL, Russell DM, Nemazee D: Receptor editing in self-reactive bone marrow B cells. J Exp Med 1993;177:1009–1020.

    Article  PubMed  CAS  Google Scholar 

  67. Radic MZ, Erikson J, Litwin S, Weigert M: B lymphocytes may escape tolerance by revising their antigen receptors. J Exp Med 1993; 177:1165–1173.

    Article  PubMed  CAS  Google Scholar 

  68. Gay D, Saunders T, Camper S, Weigert M: Receptor editing: an approach by autoreactive B cells to escape tolerance. J Exp Med 1993;177:999–1008.

    Article  PubMed  CAS  Google Scholar 

  69. Melamed D, Benschop RJ, Cambier JC, Nemazee D: Developmental regulation of B lymphocyte immune tolerance compartmentalizes clonal selection from receptor selection. Cell 1998;92:173–182.

    Article  PubMed  CAS  Google Scholar 

  70. Demengeot J, Vasconcellos R, Modigliani Y, Grandien A, Coutinho A: B lymphocyte sensitivity to IgM receptor ligation is independent of maturation stage and locally determined by macrophage-derived IFN-B. Int Immunol 1997;9:1677–1685.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. University of Pennsylvania School of Medicine, Room 311 BRBII 421 Curie Blyd, 19104, Philadelphia, PA

    John G. Monroe PhD, Gregory Bannish, Ezequiel M. Fuentes-Panana, Leslie B. King, Peter C. Sandel, James Chung & Richard Sater

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  1. John G. Monroe PhD
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  2. Gregory Bannish
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  3. Ezequiel M. Fuentes-Panana
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  4. Leslie B. King
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  5. Peter C. Sandel
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  6. James Chung
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  7. Richard Sater
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Correspondence to John G. Monroe PhD.

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Monroe, J.G., Bannish, G., Fuentes-Panana, E.M. et al. Positive and negative selection during B lymphocyte development. Immunol Res 27, 427–442 (2003). https://doi.org/10.1385/IR:27:2-3:427

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