Immunologic Research

, Volume 26, Issue 1–3, pp 45–54 | Cite as

Role of CD19 signal transduction in B cell biology

Article

Abstract

Knockout studies have established an important role for the B lymphocyte surface protein CD19 in physiology. Previous studies by us and others have examined how CD19 might function at the biochemical level, with focus on the cytoplasmic tyrosines. We have mapped multiple different molecular associations with these tyrosines. However, the major question in CD19 signaling is, how do these tyrosines relate to what happens in vivo? To address this issue, we created mice expressing only mutant forms of CD19. Our initial studies have found that most CD19 function in vivo is dependent on two of these cytoplasmic tyrosines, Y482 and Y513. However, the signaling defects in cells expressing this mutation are subtle. They demonstrate that how CD19 signals depends on how it is ligated, and that CD19 signals by more than one mechanism. These observations in primary cells give insights into how CD19 functions at the molecular level and likely explain some of the differences in CD19 function that have been reported in vivo.

Key words

CD19 Signal transduction B lymphocytes Antibodies Calcium 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Fearon DT, Carter RH: The CD19/CR2/TAPA-1 complex of B lymphocytes: linking natural to acquired immunity. Annu Rev Immunol 1995;13:127–149.PubMedCrossRefGoogle Scholar
  2. 2.
    Matsumoto AK, Martin DR, Carter RH, Klickstein LB, Ahearn J, Fearon DT: Functional dissection of the CD21/CD19/TAPA-1/Leu-13 complex of B lymphocytes. J Exp Med 1993;178:1407–1417.PubMedCrossRefGoogle Scholar
  3. 3.
    Fearon DT, Carroll MC: Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex. Annu Rev Immunol 2000;18:393–422.PubMedCrossRefGoogle Scholar
  4. 4.
    Engel P, Zhou L-J, Ord DC, Sato S, Koller B, Tedder TF: Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Immunity 1995;3:39–50.PubMedCrossRefGoogle Scholar
  5. 5.
    Sato S, Ono N, Steeber D, Pisetsky D, Tedder T: CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity. J Immunol 1996;157:4371–4378.PubMedGoogle Scholar
  6. 6.
    Martin F, Kearney JF: Positive selection from newly formed to marginal zone B cells depends on the rate of clonal production, CD19, and bik. Immunity 2000;12: 39–49.PubMedCrossRefGoogle Scholar
  7. 7.
    Martin F, Kearney JF: B-cell subsets and the mature preimmune repertoire: marginal zone and B1 B cells aspart of a “natural immune memory”, Immunol Rev 2000;175:70–79.PubMedCrossRefGoogle Scholar
  8. 8.
    Fischer MB, Goerg S, Shen L, Prodeus AP, Goodnow CC, Kelsoe G, Carroll MC: Dependence of germinal center B cells on expresion of CD21/CD35 for survival. Science 1998;280:582–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Molina H, Holers V, Li B, Fang Y-F, Mariathasan S, Goellner J, Strauss-Schoenberger J, Karr R, Chaplin D: Markedly impaired humoral immune response in mice deficient incomplement receptors 1 and 2. Proc Natl Acad Sci USA 1996;93:3357–3361.PubMedCrossRefGoogle Scholar
  10. 10.
    Carter RH, Fearon DT: CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 1992;256:105–107.PubMedCrossRefGoogle Scholar
  11. 11.
    O'Rourke LM, Tooze R, Turner M, Sandoval DM, Carter RH, Tybulewicz VLJ, Fearon DT: CD19 as a membrane-anchored adaptor protein of B lymphocytes: costimulation of lipid and protein kinases by recruitment of Vay. Immunity 1998;8:635–645.PubMedCrossRefGoogle Scholar
  12. 12.
    Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT: C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 1996;271:348–350.PubMedCrossRefGoogle Scholar
  13. 13.
    Baiu DC, Prechl J, Tchorbanov A, Molina HD, Endei A, Sulica A, Capel PJ, Hazenbos WL: Modulation of the humoral immune response by antibody-mediated antigen targeting to complement receptors and Fc receptors. J Immunol 1999;162:3125–3130.PubMedGoogle Scholar
  14. 14.
    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;376:352–355.PubMedCrossRefGoogle Scholar
  15. 15.
    Ochsenbein AF, Pinschewer DD, Odermatt B, Carroll MC, Hengartner H, Zinkernagel RM: Protective T cell-independent antiviral antibody responses are dependent on complement. J Exp Med 1999;190:1165–1174.PubMedCrossRefGoogle Scholar
  16. 16.
    Fehr T, Rickert RC, Odermatt B, Roes J, Rajewsky K, Hengartner H, Zinkernagel RM. Antiviral protection and germinal center formation, but impaired B cell memory in the absence of CD19. J Exp Med 1998;188:145–155.PubMedCrossRefGoogle Scholar
  17. 17.
    Sato S, Hasegawa M, Fujimoto M, Tadder TF, Takehara K: Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol 2000;165: 6635–6643.PubMedGoogle Scholar
  18. 18.
    Inaoki M, Sato S, Weintraub BC, Goodnow CC, Tedder TF: DC19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes. J Exp Med 1997;186:1923–1931.PubMedCrossRefGoogle Scholar
  19. 19.
    Carter RH, Tuveson DA, Park DJ, Rhee SG, Fearon DT: The CD19 complex of B lymphocytes: activation of phospholipase C by a protein tyrosine kinase-dependent pathway that can be enhanced by the membrane IgM complex. J Immunol 1991;147:3663–3671.PubMedGoogle Scholar
  20. 20.
    Cherukuri A, Cheng P, Sohn H, Pierce S: The CD19/CD21 Complex functions to prolong B cell antigen receptor signaling from lipid rafts. Immunity 2001;14:168–179.Google Scholar
  21. 21.
    Zhou LJ, Ord DC, Hughes AL, Tedder TF: Structure and domain organization of the CD19 antigen of human, mouse, and guinea pig B lymphocytes: conservation of the extensive cytoplasmic domain. J Immunol 1991;147:1424–1432.PubMedGoogle Scholar
  22. 22.
    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;260:986–989.PubMedCrossRefGoogle Scholar
  23. 23.
    Scharenberg AM, Kinet JP: Ptdlns-3,4,5-P3: a regulatory nexus between tynosine kinases and sustained calcium signals. Cell 1998;94:5–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Li X, Sandoval D, Freeberg L, Carter RH: Role of CD19 tyrosine 391 in synergistic activation of B lymphocytes by coligation of CD19 and membrane 1g. J Immunol 1997;158:5649–5657.PubMedGoogle Scholar
  25. 25.
    Brooks SR, Li X, Yolanakis 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;164:3123–3131.PubMedGoogle Scholar
  26. 26.
    Fujimoto M, Fujimoto Y, Poe J, Jansen P, Lowell C, DeFranco A, Tedder T: CD19 regulates Src family protein tyrosine kinase activation in B lymphocytes through processive amplification. Immunity 2000;13:46–57.CrossRefGoogle Scholar
  27. 27.
    Chalupny NJ, Aruffo A, Esselstyn JM, Chan PY, Bajorath J, Blake J, Gilliland LK, Ledbetter JA, Tepper MA: Specific binding of Fyn and phosphatidylinositol 3-kinase to the B cell surface glycoprotein CD19 through their src homology 2 domains. Eur J Immunol 1995; 25:2978–2984.PubMedCrossRefGoogle Scholar
  28. 28.
    Carter RH, Spycher MO, Ng YC, Hoffman R, Fearon DT: Synergistic interaction between complement receptor type 2 and membrane IgM on B lymphocytes. J Immunol 1988;141:457–463.PubMedGoogle Scholar
  29. 29.
    Matsumoto AK, Kopicky-Burd J, Carter RH, Tuveson DA, Tedder TF, Fearon DT: Intersection of the complement and immune systems: a signal transduction complex of the B lymphocyte-containing complement receptor type 2 and CD19. J Exp Med 1991;173:55–64.PubMedCrossRefGoogle Scholar
  30. 30.
    Li X, Carter RH: Convergence of CD19 and B cell antigen receptor signals in the ERK2 activation cascade. J Immunol 1998;161:5901–5908.PubMedGoogle Scholar
  31. 31.
    Li X, Carter RH: CD19 signal transduction in normal human B cells: linkage to downstream pathways requires phosphatidy linositol 3-kinase, protein kinase C and Ca2+. Eur J Immunol 2000;30: 1576–1586.PubMedCrossRefGoogle Scholar
  32. 32.
    Zhang R, Alt FW, Davidson L, Orkin SH, Swat W: Defective signalling through the T- and B-cell antigen receptors in lymphoid cells lacking the vav proto-oncogene. Nature 1995;374:470–473.PubMedCrossRefGoogle Scholar
  33. 33.
    Tarakhovsky A, Turner M, Schaal S, Mee PJ, Duddy LP, Rajwsky K, Tybulewicz VLJ: Defective antigen-receptor mediated proliferation of B and T cells in the absence of Vav. Nature 1995;374:467–470.PubMedCrossRefGoogle Scholar
  34. 34.
    Crespo P, Bustelo X, Aaroson D, Coso O, Lopez-Barahoma M, Barbacid M, Gutkind J: Rac-1 dependent stimulation of the JNK/SAPK signaling pathway by Vav. Oncogene 1996;13:455–460.PubMedGoogle Scholar
  35. 35.
    Buhl AM, Pleiman CM, Rickert RC, Cambier JC: Qualitativ regulation of B cell antigen receptor signaling by CD19: selective requirement for P13-kinase activation, inositol-1,4-5-trisphosphate production and Ca2+ mobilization. J Exp Med 1997;186:1897–1910.PubMedCrossRefGoogle Scholar
  36. 36.
    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; 162:4438–4446.PubMedGoogle Scholar
  37. 37.
    Fujimoto M, Poe JC, Inaoki M, Tedder TF: CD19 regulates B lymphocyte responses to transmembrane signals. Semin Immunol 1998;10:267–277.PubMedCrossRefGoogle Scholar
  38. 38.
    Fujimoto M, Poe JC, Jansen PJ, Sato S, Tedder TF: CD19 amplifies B lymphocyte signal transduction by regulating Src-family protein tyrosine kinase activation. J Immunol 1999;162:7088–7094.PubMedGoogle Scholar
  39. 39.
    Carter RH, Park DG, Rhee SG, Feanon DT: Tyrosine phosphorylation of phospholipase C induced by membrane immunoglobulin in B lymphocytes. Proc Natl Acad Sci USA 1991;88:2745–2749.PubMedCrossRefGoogle Scholar
  40. 40.
    Nishizuka Y: Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 1992;258:607–614.PubMedCrossRefGoogle Scholar
  41. 41.
    Schonwasser DC, Marias RM, Marchall CJ, Parker PJ: Activation of the mitogen-activated protein in kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol Cell Biol 1998;18:790–798.PubMedGoogle Scholar
  42. 42.
    Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ: Protein kinase C isotypescontrolled by phosphoinositide 3-kinase through the protein in kinase PDK1. Science 1982;281:2042–2045.CrossRefGoogle Scholar
  43. 43.
    Barbazuk SM, Gold MR: Protein kinase C-delta is a larget of B-cell antigen receptor signaling. Immunol Lett 1999;69:259–267.PubMedCrossRefGoogle Scholar
  44. 44.
    Morrow TA, Muljo SA, Zhang J, Hardwick JM, Schlissel MS: Pro-B-cell-specific transcription and proapoptotic function of protein kinase Ceta. Mol Cell Biol 1999; 19:5608–5618.PubMedGoogle Scholar
  45. 45.
    King LB, Norvell A, Monroe JG: Antigen receptor-induced signal transduction imbalances associated with the negative selection of immature B cells. J Immunol 1999;162:2655–2662.PubMedGoogle Scholar
  46. 46.
    Chan VW, Mecklenbrauker I, Sul, I, Texido, G, Leitges M, Carsetti R, Lowell CA, Rajewsky K, Miyake K, Tarakhowsky A. The molecular mechanism of B cell activation by toll-like receptor protein RP-105. J Exp Med 1998;188:93–101.PubMedCrossRefGoogle Scholar
  47. 47.
    Deehan MR, Harnett MM, Hamett W: A filarial nematode secreted product differentially modulates expression and activation of protein kinase C isoformsin B lymphocytes. J Immunol 1997;159:6105–6111.PubMedGoogle Scholar
  48. 48.
    Leitges M, Schmedt C, Guinamard R, Davoust J, Schaal S, Stabel S, Tarakhovsky A: Immunodeficiency in protein kinase cbeta-deficient mice. Science 1996;273:788–791.PubMedCrossRefGoogle Scholar
  49. 49.
    Carballo E, Colomer D, Vives-Corrons JL, Blackshear PJ, Gil J: Characterization and parification of a protein kinase C substrate in human B cells. Identification as lymphocyte-specific protein I (LSPI). J Immunol 1996;156: 1709–1713.PubMedGoogle Scholar
  50. 50.
    Sidorenko S, Law C-L, Klaus S, Chandran K, Takata M, Kurosaki T, Clark E: Protein kinase C μ associates with the B cell antigen receptor complex and regulates lymphocyte signaling. Immunity 1996;5:353–363.PubMedCrossRefGoogle Scholar
  51. 51.
    Uckun F, Burkhardt AL, Jarvis L, Stealey B, Dibirdik I, Myers DE, Tuel-Ahlgren L, Bolen JB: Signal transduction through the CD19 receptor during discrete developmental stages of human B-cell ontogeny. J Biol Chem 1993;268: 21,172–21,184.Google Scholar

Copyright information

© Humana Press Inc. 2002

Authors and Affiliations

  1. 1.Departments of Medicine and MicrobiologyUniversity of Alabama at BirminghamBirmingham

Personalised recommendations