Immunologic Research

, Volume 25, Issue 2, pp 155–166 | Cite as

Positive and negative roles of CD72 in B cell function

  • Hsin-Jung Wu
  • Subbarao Bondada


Regulation of B cell activation depends on integration of signals transmitted by the B cell receptor (BCR) and a variety of co-receptors. CD72 is a B cell co-receptor that is expressed in all stages of B cell development except plasma cells. Ligation of CD72 enhances B cell growth and differentiation. Recently, the class IV semaphoring, CD 100, has been identified as the natural ligand for CD72. Cytoplasmic domain of CD72 has been shown to be associated with SHP-1 leading to the proposal that the positive effects of CD72 on B cell response may result from sequestration of negative signals from BCR. However, association of CD72 with Grb2 and/or CD19 suggests that CD72 could transmit positive signals. Based on these data, we propose a dual signaling model of CD72.

Key Words

Cellular proliferation Signal transduction Co-stimulatory molecules Cell surface molecules Co-receptor 


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  1. 1.
    Subbarac B, Baluyut AR, Muthusamy N: Functionally important B cell surface molecules. In T-Cell Dependent And Independent B-Cell Activation. Snow EC ed. 1990: CRC Press, Inc., Boca Raton, p. 39Google Scholar
  2. 2.
    Gordon J: B-cell signalling via the C-type lectins CD23 and CD72. Immunol Today 1994;15:411.PubMedCrossRefGoogle Scholar
  3. 3.
    Tedder TF, Inaoki M, Sato S: The CD19-CD21 complex regulates signal transduction thresholds governing humoral immunity and autoimmunity. Immunity 1997;6:107.PubMedCrossRefGoogle Scholar
  4. 4.
    Lund F, Solvason N, Grimaldi JC, Parkhouse RM, Howard M: Murine CD38: an immunoregulatory ectoenzyme. Immunol Today 1995;16:469.PubMedCrossRefGoogle Scholar
  5. 5.
    Banchereau J, Bazan F, Blanchard D, Briere F, Galizzi JP, van Kooten C, Liu YJ, Rousset F, Saeland S: The CD40 antigen and its ligand. Annu Rev Immunol 1994;12:881.PubMedCrossRefGoogle Scholar
  6. 6.
    Bikah G, Carey J, Ciallella JR, Tarakhovsky A, Bondada S: CD5-mediated negative regulation of antigen receptor-induced growth signals in B-1 B cells. Science 1996;274:1906.PubMedCrossRefGoogle Scholar
  7. 7.
    Amigorena S, Bonnerot C, Drake JR, Choquet D, Humziker W, Guillet JG, Weibster P, Sautes C, Mellman I, Fridman WH: Cytoplasmic domain heterogeneity and functions of IgG Fc receptors in Blymphocytes. Science 1992;256:1808.PubMedCrossRefGoogle Scholar
  8. 8.
    Ono MO, Bolland S, Yanagi S, Kurosaki S, Ravetch T, IV: Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. Cell 1997;90:293.PubMedCrossRefGoogle Scholar
  9. 9.
    Maeda AK, Ono M, Takai M, Kurosaki T: Requirement of SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 for paired immunoglobulin-like receptor B: (PIR-B)-mediated inhibitory signal. J Exp Med 1998; 187:1355.PubMedCrossRefGoogle Scholar
  10. 10.
    Doody GM, Justement LB, Delibrias CC, Matthews RJ, Lin J, Thomas ML, Fearon DT: A role in B cell activation for CD22 and the proteintyrosine phosphatase SHP. Science 1995;269:242.PubMedCrossRefGoogle Scholar
  11. 11.
    Subbarao B, Mosier DE: Induction of B lymphocyte proliferation without antibody secretion by monoclonal anti-Ly b2 antibody. J Immunol 1983;130:2033.PubMedGoogle Scholar
  12. 12.
    Yakura H, Shen F-W, Bourcet E, Boyse EA: Evidence that Lyb-2 is critical to specific activation of B cells before they become responsive to T and other signals. J Exp Med 1982;155:1309.PubMedCrossRefGoogle Scholar
  13. 13.
    Adachi T, Flaswinkel H, Yakura H, Reth M, Tsubata T: The B cell surface protein CD72 recruits the lyrosine phosphatase SHP-1 upon tyrosine phosphorylation. J Immunol 1998;160:4662.PubMedGoogle Scholar
  14. 14.
    Venkataraman C, Muthusamy N, Muthukkumar S, Bondada S: Activation of lyn, blk and btk but not sykin CD72 stimulated B lymphocytes. J Immunol 1998;160:3322.PubMedGoogle Scholar
  15. 15.
    Wu Y, Nadler MJ, Brennan LA, et al.: The B-cell transmembrane protein CD72 binds to and is an in vivo substrate of the protein tyrosine phosphatase SHP-1. Curr Biol 1998;8:1009.PubMedCrossRefGoogle Scholar
  16. 16.
    Pan C, Baumgarth N, Parnes JR: CD72-deficient micereveal nonredundant roles of CD72 in B cell development and activation. Immunity 1999;11:495.PubMedCrossRefGoogle Scholar
  17. 17.
    O'Keefe TL, Williams GT, Davies SL, Neuberger MS: Hyperresponsive B cells in CD22-deficient mice. Science 1996;274:798.PubMedCrossRefGoogle Scholar
  18. 18.
    Otipoby KL, Andersson KB, Draves KE, et al.: CD22 regulates thymus-independent responses and the lifespan of B cells. Nature 1996;384:634.PubMedCrossRefGoogle Scholar
  19. 19.
    Sato S, Miller AS, Inaoki M, et al.: CD22 is both a positive and negative regulator of B lymphocyte antigen receptor signal transduction: altered signaling in CD22-deficient mice. Immunity 1996;5:551.PubMedCrossRefGoogle Scholar
  20. 20.
    Nitschke L, Carsetti R, Ocker B, Kohler G, Lamers MC: CD22 is a negative regulator of B-cell receptor signalling. Curr Biol 1997; 7:133.PubMedCrossRefGoogle Scholar
  21. 21.
    Nakayama E, von Hoegen I, Parnes JR: Sequence of the Lyb-2 B-cell differentiation antigen defines a gene superfamily of receptors with inverted membrane orientation. Proc Natl Acad Sci USA 1989;86:1352.PubMedCrossRefGoogle Scholar
  22. 22.
    Songyang Z, Shoelson SE, McGlade J, et al.: Specific motifs recognized by the SH2 domains of Csk, 3BP 2, fps/fes GRB-2, HCP, SHC, Syk, and Vav. Mol Cell Biol 1994;14:2777.PubMedGoogle Scholar
  23. 23.
    Tung JS, Shen FW, LaRegina V, Boyse EA: Antigenic complexity and protein-structural polymorphism in the Lyb-2 system. Immunogenetics 1986;23:208.PubMedCrossRefGoogle Scholar
  24. 24.
    Robinson WH, Ying H, Miceli MC, Parnes JR: Extensive polymorphism in the extracellular domain of the mouse B cell differentiation antigen Lyb-2/CD72. J Immunol 1992;149:880.PubMedGoogle Scholar
  25. 25.
    Goitsuka R, Chen CH, Cooper MD: B cells in the bursa of fabricius express a novel C-type lectin gene. J Immunol 1997;159:31–26.Google Scholar
  26. 26.
    Ying H, Chang J-F, Parnes JR: PU.I/Spi-1 is essential for the B cell-specific activity of the mouse CD72 promoter. J Immunol 1998;160:2287.PubMedGoogle Scholar
  27. 27.
    Ying H, Healy JI, Goodnow CC, Parnes JR: Regulation of mouse CD72 gene expression during B lymphocyte development. J Immunol 1998;161:4760.PubMedGoogle Scholar
  28. 28.
    Robinson WH, TuttLandolfi MM, Parnes JR: Allele-specific expression of the mouse B-cell surface protein CD72 on T cells. Immunogenetics 1997;45:195.PubMedCrossRefGoogle Scholar
  29. 29.
    Schwarting R, Castello R, Moldenhauer G, et al.: Human Lyb-2 homolog CD72 is a marker for progenitor B-cell leukemias. Am J Hematol 1992;41:151.PubMedCrossRefGoogle Scholar
  30. 30.
    Massard G, Tongio MM, Wihlm JM, Morand G: The dendritic cell lineage: a ubiquitous antigen-presenting organization. Ann Thorac Surg 1996;61:252.PubMedCrossRefGoogle Scholar
  31. 31.
    Myers DE, Uckun FM: An anti-CD72 immunotoxin against therapy-refractory B-lineage acute lymphoblastic leukemia. Leuk Lymphoma 1995;18:119.PubMedGoogle Scholar
  32. 32.
    Subbarao B, Mosier DE: Lyb antigens and their role in B lymphocyteactivation. Immunol Rev 1982; 69:81.PubMedCrossRefGoogle Scholar
  33. 33.
    Subbarao B, Mosier DE: Activation of B lymphocytes by monovalent anti-Lyb2 antibodies. J Exp Med 1984;159:1796.PubMedCrossRefGoogle Scholar
  34. 34.
    Subbarao B, Morris J, Baluyut AR: Properties of anti-Lyb2 mediated B cell activation and the relation-ship between Lyb2 molecules and receptors for B cell stimulatory factor-1 on murine B lymphocytes. Cell Immunol 1988;112:329.PubMedCrossRefGoogle Scholar
  35. 35.
    Polla BS, Ohara J, Paul WE, et al.: Differential induction of class 11 gene expression in murine pre-B-cell lines by B-cell stimulatory factor-1 and by antibedies to B-cell surface antigens. J Mol Cell Immunol 1988;3:363.PubMedGoogle Scholar
  36. 36.
    Kamal M, Katira A, Gordon J: Stimulation of B lymphocytes via CD72 (human Lyb-2). Eur J Immunol 1991;21:1419.PubMedCrossRefGoogle Scholar
  37. 37.
    Katira A, Kamal M, Gordon J: Occupancy of CD72 (the CD5 counterstructure) enhances interleukin-4-dependent CD23 expression in resting B lymphocytes. Immunology 1992;76:422.PubMedGoogle Scholar
  38. 38.
    Yakura H, Shen FW, Boyse EA: Lyb-2 system of mouse B cells. Evidence for a role in the generation of antibody-forming cells. J Exp Med 1981;153:129.PubMedCrossRefGoogle Scholar
  39. 39.
    Snow EC, Mond JJ, Subbarao B: Enhancement by monoclonal anti-Lyb2 antibody of antigen specific B lymphocyte expansion stimulated by TNP-Ficoll and T lymphocyte-derived factors. J Immunol 1986;137:1793.PubMedGoogle Scholar
  40. 40.
    Subbarao B, Mosier DE: IsLyb-2, a B lymphocyte surface antigen, a target for a T cell-derived factor. In B and T cell tumors. Vitetta ES, Fox CF, eds. Academic Press, New York, 1982, p. 191.Google Scholar
  41. 41.
    Ogimoto M, Mizuno K, Tate G, et al.: Regulation of lipopolysaccharide-and IL-4 induced immunoglobulin heavy chain gene activation: differential roles for CD45 and Lyb-2. Int Immunol 1992;4:651.PubMedCrossRefGoogle Scholar
  42. 42.
    Nomura T, Han H, Howard MC, et al.: Antigen receptor-mediated B cell death is blocked by signaling via CD72 or treatment with dextran sulfate and is defective in autoimmunity-prone mice. Int Immunol 1996;8:867.PubMedCrossRefGoogle Scholar
  43. 43.
    Hsin-Jung Wu, Venkataraman C, Estus S, Dong C, Davis RJ, Flavell RA, Bondada S: Positive signaling through CD72 induces MAPK activation and synergizes with BCR signals to induce X id B cell proliferation. J Immunol 2001;167:1263–1273.Google Scholar
  44. 44.
    Muthusamy N, Baluyut AR, Subbarao B: Differential regulation of surface Ig- and Lyb2-mediated B cell activation by cyclic AMP. 1. Evidence for alternative regulation of signaling through two different receptors linked to phosphatidylinositol hydrolysis in murine B cells. J Immunol 1991; 147:2483.PubMedGoogle Scholar
  45. 45.
    Muthusamy N, Bondada S: Differential regulation of surface immunoglobulin and Lyb2 mediated B cell activation. II cAMP dependent (prostaglandin E2) and independent (IFN-γ) mechanisms of regulation of B lymphocyte activation. Int Immunol 1993;5:949.PubMedCrossRefGoogle Scholar
  46. 46.
    Sen G, Bikah G, Venkataraman C, Bondada S: Negative regulation of antigen receptor-mediated signaling by constitutive association of CD5 with the SHP-1 protein tyrosine phosphatase in B-1 B cells. Eur J Immunol 1999;29:3319.PubMedCrossRefGoogle Scholar
  47. 47.
    Van de Velde H, von Hoegen I, Luo W, Parnes JR, Thielemans K: The B cell surface protein CD72/Lyb-2 is the ligand for CD5. Nature 1991;351:662.PubMedCrossRefGoogle Scholar
  48. 48.
    Luo W, Van de Velde H, von Hoegen I, Parnes JR, Thielemans K: Ly-1 (CD5), a membrane glycoprotein of mouse T lymphocytes and a subset of B cells is a natural ligand of the B cell surface protein Lyb-2(CD72). J Immunol 1992; 148:1630.PubMedGoogle Scholar
  49. 49.
    Bikah G, Lynd FM, Aruffo AA, Ledbetter JA, Bondada S: A role for CD5 in cognate interactions between T cells and B cells, and identification of a novel ligand for CD5. Int Immunol 1998;10:1185.PubMedCrossRefGoogle Scholar
  50. 50.
    Biancone L, Bowen MA, Lim A, Aruffo A, Andres G, Stamenkovic I: Identification of a novel cell-surface ligand of CD5 on activated lymphocytes. J Exp Med 1996; 184:811.PubMedCrossRefGoogle Scholar
  51. 51.
    Calvo J, Places L, Padilla O, et al.: Interaction of recombinant and natural soluble CD5 forms with an alternative cell surface ligand. Eur J Immunol 1999;29:2119.PubMedCrossRefGoogle Scholar
  52. 52.
    Kumanogoh A, Watanabe C, Lee I, et al.: Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100. A novel mechanism for regulating B cell signaling. Immunity 2000; 13:621.PubMedCrossRefGoogle Scholar
  53. 53.
    Delaire S, Elhabazi A, Bensussan A, Boumsell L: CD100 is a leukocyte semaphorin. Cell Mol Life Sci 1998;54:1265.PubMedCrossRefGoogle Scholar
  54. 54.
    Shi W, Kumanogoh A, Watanabe C, et al.: The class IV semaphorin CD100 plays nonredundant roles in the immune system. Defective B and T cell activation in CD100-deficient mice. Immunity 2000; 13:633.PubMedCrossRefGoogle Scholar
  55. 55.
    Grupp SA, Harmony JA, Baluyut AR, Subbarao B: Early events in B-cell activation: Anti-Lyb2, but not BSF-1, induces a phosphatidylinositol response in murine B cells. Cell Immunol 1987;110:131.PubMedCrossRefGoogle Scholar
  56. 56.
    Justement LB: Signal transduction via the B-cell antigen receptor: the role of protein tyrosine kinases and protein tyrosine phosphatases. Curr Top Microbiol Immunol 2000;245:1.PubMedGoogle Scholar
  57. 57.
    Venkataraman C, Lu P-J, Buhl AM, Chen C-S, Cambier JC, Bondada S: CD72 mediated B cell activation involves recruitment of CD19 and activation of phosphatidylinositol 3-kinase. Eur J Immunol 1998;28:3003.PubMedCrossRefGoogle Scholar
  58. 58.
    Seger R, Krebs EG: The MAPK signaling cascade. Faseb J 1995; 9:726.PubMedGoogle Scholar
  59. 59.
    Adachi T, Wakabayashi C, Nakayama T, Yakura H, Tsubata T: CD72 negatively regulates signaling through the antigen receptor of B cells. J Immunol 2000;164:1223.PubMedGoogle Scholar
  60. 60.
    Pani G, Siminovitch KA, Paige CJ: The motheaten mutation rescues B cell signaling and development in CD45-deficient mice. J Exp Med 1997;186:581.PubMedCrossRefGoogle Scholar
  61. 61.
    Scharenberg AM, Kinet J-P: The emerging field of receptor-mediated inhibitory signaling: SHP or SH1P. Cell 1996;87:961.PubMedCrossRefGoogle Scholar
  62. 62.
    Glynne R, Akkaraju S, Healy JI, Rayner J, Goodnow CC, Mack DH: How self-tolerance and the immunosuppressive drug FK-506 prevent B-cell mitogenesis. Nature 2000; 403:672.PubMedCrossRefGoogle Scholar
  63. 63.
    Fusaki N, Tomita S, Wu Y et al.: BLNK is associated with the CD72/SHP-1/grb2 complex in the WEHI231 cell line after membrane IgM cross-linking. Eur J Immunol 2000;30:1326.PubMedCrossRefGoogle Scholar
  64. 64.
    Chaouchi N, Vazquez A, Galanaud P, Leprince C: B cell antigen receptor-mediated apoptosis. Importance of accessory molecules CD19 and CD22, and of surface IgM cross-linking. J Immunol 1995;154:3096.PubMedGoogle Scholar
  65. 65.
    Tuscano JM, Riva A, Toscano SN, Tedder TF, Kehrl JH: CD22 cross-linking generates B-cell antigen receptor-independent signals that activate the JNK/SAPK signaling cascade. Blood 1999;94:1382.PubMedGoogle Scholar
  66. 66.
    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.PubMedCrossRefGoogle Scholar
  67. 67.
    Solvason N, Wu WW, Kabra N et al.: Transgene expression of bcl-xL permits anti-immunoglobulin (Ig)-induced proliferation in xid B cells. J Exp Med 1998; 187:1081.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2002

Authors and Affiliations

  • Hsin-Jung Wu
    • 1
    • 2
  • Subbarao Bondada
    • 1
    • 2
  1. 1.Department of Microbiology and ImmunologyUniversity of KentuckyLexington
  2. 2.The Sanders Brown Center on AgingUniversity of KentuckyLexington

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