Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Hsin-Jung WuEmail author
  • Natarajan Muthusamy
  • Subbarao Bondada
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_461


Historical Background

B lymphocytes express several surface molecules other than the B cell receptors (BCR) that function as markers of differentiation as well as molecules that can fine tune BCR signaling. Current research has identified a function for most antigens that were previously classified as markers of lymphocyte differentiation. CD72 is one such molecule that was originally discovered as a marker of B cell differentiation using conventional serological and classical genetic techniques. Subsequently generation of monoclonal antibodies helped its definition as a molecule that can affect B cell growth and differentiation on its own or in the context of BCR signaling. Initially Sato and Boyse described an activity in sera from C3H.I mice immunized with 1.29 ascites tumor cells that reacted only with a subset of spleen cells after it was absorbed to remove an unknown reactivity. Subsequently the cell type in the spleen...

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  1. Adachi T, Wakabayashi C, Nakayama T, Yakura H, Tsubata T. CD72 negatively regulates signaling through the antigen receptor of B cells. J Immunol. 2000;164:1223–9.PubMedCrossRefGoogle Scholar
  2. Akatsu C, Shinagawa K, Numoto N, Liu Z, Ucar AK, Aslam M, Phoon S, Adachi T, Furukawa K, Ito N, Tsubata T. CD72 negatively regulates B lymphocyte responses to the lupus-related endogenous toll-like receptor 7 ligand Sm/RNP. J Exp Med. 2016;213:2691–706.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Alcón VL, Luther C, Balce D, Takei F. B-cell co-receptor CD72 is expressed on NK cells and inhibits IFN-γ production but not cytotoxicity. Eur J Immunol. 2009;39:826–32.PubMedCrossRefGoogle Scholar
  4. Berland R, Fernandez L, Kari E, Han JH, Lomakin I, Akira S, Wortis HH, Kearney JF, Ucci AA, Imanishi-Kari T. Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. Immunity. 2006;25:429–40.PubMedCrossRefGoogle Scholar
  5. Besliu A, Banica L, Predeteanu D, Vlad V, Ionescu R, Pistol G, Opris D, Berghea F, Stefanescu M, Matache C. Peripheral blood lymphocytes analysis detects CD100/SEMA4D alteration in systemic sclerosis patients. Autoimmunity. 2011;44:427–36.PubMedCrossRefGoogle Scholar
  6. 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;10:1185–96.PubMedCrossRefGoogle Scholar
  7. Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity. 2006;25:417–28.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Deaglio S, Vaisitti T, Bergui L, Bonello L, Horenstein AL, Tamagnone L, Boumsell L, Malavasi F. CD38 and CD100 lead a network of surface receptors relaying positive signals for B-CLL growth and survival. Blood. 2005;105:3042–50.PubMedCrossRefGoogle Scholar
  9. Eriksson EM, Milush JM, Ho EL, Batista MD, Holditch SJ, Keh CE, Norris PJ, Keating SM, Deeks SG, Hunt PW, Martin JN, Rosenberg MG, Hecht FM, Nixon DF. Expansion of CD8+ T cells lacking Sema4D/CD100 during HIV-1 infection identifies a subset of T cells with decreased functional capacity. Blood. 2012;119:745–55.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Fusaki N, Tomita S, Wu Y, Okamoto N, Goitsuka R, Kitamura D, Hozumi N. BLNK is associated with the CD72/SHP-1/grb2 complex in the WEHI231 cell line after membrane IgM cross-linking. Eur J Immunol. 2000;30:1326–30.PubMedCrossRefGoogle Scholar
  11. Gustin SE, Thien CB, Langdon WY. Cbl-b is a negative regulator of inflammatory cytokines produced by IgE-activated mast cells. J Immunol. 2006;177:5980–9.PubMedCrossRefGoogle Scholar
  12. Han S, Zhuang H, Shumyak S, Yang L, Reeves WH. Mechanisms of autoantibody production in systemic lupus erythematosus. Front Immunol. 2015;6:228.PubMedPubMedCentralCrossRefGoogle Scholar
  13. He Y, Guo Y, Zhou Y, Zhang Y, Fan C, Ji G, Wang Y, Ma Z, Lian J, Hao C, Yao ZQ, Jia Z. CD100 up-regulation induced by interferon-alpha on B cells is related to hepatitis C virus infection. PLoS One. 2014;9:e113338.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Hitomi Y, Tsuchiya N, Kawasaki A, Kyogoku C, Ohashi J, Suzuki T, Fukazawa T, Bejrachandra S, Siriboonrit U, Chandanayingyong D, Suthipinittharm P, Tsao BP, Hashimoto H, Honda Z-I, Tokunaga K. CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B. Hum Mol Genet. 2004 Dec 1;13(23):2907–17.Google Scholar
  15. Hitomi Y, Adachi T, Tsuchiya N, Honda Z-I, Tokunaga K, Tsubata T. Human CD72 splicing isoform responsible for resistance to systemic lupus erythematosus regulates serum immunoglobulin level and is localized in endoplasmic reticulum. BMC Immunol. 2012;13:72.PubMedPubMedCentralCrossRefGoogle Scholar
  16. James JA, Gross T, Scofield RH, Harley JB. Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: Sm B/B’-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity. J Exp Med. 1995;181:453–61.PubMedCrossRefGoogle Scholar
  17. Kataoka TR, Kumanogoh A, Bandara G, Metcalfe DD, Gilfillan AM. CD72 negatively regulates KIT-mediated responses in human mast cells. J Immunol. 2010;184:2468–75.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Kataoka TR, Kumanogoh A, Hirata M, Moriyoshi K, Ueshima C, Kawahara M, Tsuruyama T, Haga H. CD72 regulates the growth of KIT-mutated leukemia cell line Kasumi-1. Sci Rep. 2013;3:2861.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Kataoka TR, Kumanogoh A, Fukuishi N, Ueshima C, Hirata M, Moriyoshi K, Tsuruyama T, Haga H. CD72 negatively regulates mouse mast cell functions and down-regulates the expression of KIT and FcepsilonRIalpha. Int Immunol. 2015;27:95–103.PubMedCrossRefGoogle Scholar
  20. Kikutani H, Kumanogoh A. Semaphorins in interactions between T cells and antigen-presenting cells. Nat Rev Immunol. 2003;3:159–67.PubMedCrossRefGoogle Scholar
  21. Kuklina EM, Baidina TV, Danchenko IY, Nekrasova IV. Semaforin Sema4D in the immune system in multiple sclerosis. Bull Exp Biol Med. 2014;157:234–7.PubMedCrossRefGoogle Scholar
  22. Kumanogoh A, Kikutani H. Biological functions and signaling of a transmembrane semaphorin, CD100/Sema4D. Cell Mol Life Sci. 2004;61:292–300.PubMedCrossRefGoogle Scholar
  23. Kumanogoh A, Shikina T, Watanabe C, Takegahara N, Suzuki K, Yamamoto M, Takamatsu H, Prasad DV, Mizui M, Toyofuku T, Tamura M, Watanabe D, Parnes JR, Kikutani H. Requirement for CD100-CD72 interactions in fine-tuning of B-cell antigen receptor signaling and homeostatic maintenance of the B-cell compartment. Int Immunol. 2005;17:1277–82.PubMedCrossRefGoogle Scholar
  24. Li DH, Winslow MM, Cao TM, Chen AH, Davis CR, Mellins ED, Utz PJ, Crabtree GR, Parnes JR. Modulation of peripheral B cell tolerance by CD72 in a murine model. Arthritis Rheum. 2008;58:3192–204.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Liu B, Ma Y, Yi J, Xu Z, Zhang YS, Zhang C, Zhuang R, Yu H, Wang J, Yang A, Zhang Y, Jin B. Elevated plasma soluble Sema4D/CD100 levels are associated with disease severity in patients of hemorrhagic fever with renal syndrome. PLoS One. 2013;8:e73958.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Liu B, Ma Y, Zhang Y, Zhang C, Yi J, Zhuang R, Yu H, Yang A, Zhang Y, Jin B. CD8low CD100- T cells identify a novel CD8 T cell subset associated with viral control during human hantaan virus infection. J Virol. 2015;89:11834–44.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Lu J, Li J, Zhu TQ, Zhang L, Wang Y, Tian FF, Yang H. Modulation of B cell regulatory molecules CD22 and CD72 in myasthenia gravis and multiple sclerosis. Inflammation. 2013;36:521–8.PubMedCrossRefGoogle Scholar
  28. Mimori K, Kiyokawa N, Taguchi T, Suzuki T, Sekino T, Nakajima H, Saito M, Katagiri YU, Isoyama K, Yamada K, Matsuo Y, Fujimoto J. Costimulatory signals distinctively affect CD20- and B-cell-antigen-receptor-mediated apoptosis in Burkitt’s lymphoma/leukemia cells. Leukemia. 2003;17:1164–74.PubMedCrossRefGoogle Scholar
  29. Mizui M, Kumanogoh A, Kikutani H. Immune semaphorins: novel features of neural guidance molecules. J Clin Immunol. 2009;29:1–11.PubMedCrossRefGoogle Scholar
  30. Myers DE, Uckun FM. An anti-CD72 immunotoxin against therapy-refractory B-lineage acute lymphoblastic leukemia. Leuk Lymphoma. 1995;18:119–22.PubMedCrossRefGoogle Scholar
  31. 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;86:1352–6.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Ogimoto M, Ichinowatari G, Watanabe N, Tada N, Mizuno K, Yakura H. Impairment of B cell receptor-mediated Ca2+ influx, activation of mitogen-activated protein kinases and growth inhibition in CD72-deficient BAL-17 cells. Int Immunol. 2004;16:971–82.PubMedCrossRefGoogle Scholar
  33. Oishi H, Tsubaki T, Miyazaki T, Ono M, Nose M, Takahashi S. A bacterial artificial chromosome transgene with polymorphic Cd72 inhibits the development of glomerulonephritis and vasculitis in MRL-Faslpr lupus mice. J Immunol. 2013;190:2129–37.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Pan C, Baumgarth N, Parnes JR. CD72-deficient mice reveal nonredundant roles of CD72 in B cell development and activation. Immunity. 1999;11:495–506.PubMedCrossRefGoogle Scholar
  35. Planken EV, Van de Velde H, Falkenburg JH, Thielemans K, Willemze R, Kluin-Nelemans JC. Selective response of CD5+ B cell malignancies to activation of the CD72 antigen. Clin Immunol Immunopathol. 1998;87:42–9.PubMedCrossRefGoogle Scholar
  36. 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;149:880–6.PubMedPubMedCentralGoogle Scholar
  37. Robinson WH, Landolfi MMT, Schafer H, Parnes JR. Biochemical identity of the mouse Ly-19.2 and 32.2 alloantigens with the B cell differentiation antigen Lyb-2/CD72. J Immunol. 1993;151:4764–72.PubMedPubMedCentralGoogle Scholar
  38. Rojas A, Xu F, Rojas M, Thomas JW. Structure and function of CD72 in the non-obese diabetic (NOD) mouse. Autoimmunity. 2003;36:233–9.PubMedCrossRefGoogle Scholar
  39. Sato H, Boyse EA. A new alloantigen expressed selectively on B cells: the Lyb-2 system. Immunogenetics. 1976;3:565–72.CrossRefGoogle Scholar
  40. Schwarting R, Castello R, Moldenhauer G, Pezzutto A, von Hoegen I, Ludwig WD, Parnes JR, Dorken B. Human Lyb-2 homolog CD72 is a marker for progenitor B-cell leukemias. Am J Hematol. 1992;41:151–8.PubMedCrossRefGoogle Scholar
  41. Subbarao B, Mosier DE. Induction of B lymphocyte proliferation without antibody secretion by monoclonal anti-Lyb2 antibody. J Immunol. 1983;130:2033–7.PubMedPubMedCentralGoogle Scholar
  42. Tung JS, Shen FW, LaRegina V, Boyse EA. Antigenic complexity and protein-structural polymorphism in the Lyb-2 system. Immunogenetics. 1986;23:208–10.PubMedCrossRefGoogle Scholar
  43. Vadasz Z, Haj T, Balbir A, Peri R, Rosner I, Slobodin G, Kessel A, Toubi E. A regulatory role for CD72 expression on B cells in systemic lupus erythematosus. Semin Arthritis Rheum. 2014;43:767–71.PubMedCrossRefGoogle Scholar
  44. Vadasz Z, Goldeberg Y, Halasz K, Rosner I, Valesini G, Conti F, Perricone C, Sthoeger Z, Bezalel SR, Tzioufas AG, Levin NA, Shoenfeld Y, Toubi E. Increased soluble CD72 in systemic lupus erythematosus is in association with disease activity and lupus nephritis. Clin Immunol. 2016;164:114–8.PubMedCrossRefGoogle Scholar
  45. Wu H-J. The positive signaling role of CD72 in B lymphocyte activation and function (doctoral thesis). In: Microbiology, immunology and molecular genetics. University of Kentucky, Lexington; 2002.Google Scholar
  46. Wu H-J, Bondada S. Positive and negative roles of CD72 in B cell function. Immunol Res. 2002;25:155–66.PubMedCrossRefGoogle Scholar
  47. Wu HJ, Bondada S. CD72, a coreceptor with both positive and negative effects on B lymphocyte development and function. J Clin Immunol. 2009;29:12–21.PubMedCrossRefGoogle Scholar
  48. Wu Y, Nadler MJ, Brennan LA, Gish GD, Timms JF, Fusaki N, Jongstra-Bilen J, Tada N, Pawson T, Wither J, Neel BG, Hozumi N. The B-cell transmembrane protein CD72 binds to and is an in vivo substrate of the protein tyrosine phosphatase SHP-1. Curr Biol. 1998;8:1009–17.PubMedCrossRefGoogle Scholar
  49. Wu HJ, Venkataraman C, Estus S, Dong C, Davis RJ, Flavell RA, Bondada S. Positive signaling through CD72 induces mitogen-activated protein kinase activation and synergizes with B cell receptor signals to induce X-linked immunodeficiency B cell proliferation. J Immunol. 2001;167:1263–73.PubMedCrossRefGoogle Scholar
  50. Xu M, Hou R, Sato-Hayashizaki A, Man R, Zhu C, Wakabayashi C, Hirose S, Adachi T, Tsubata T. Cd72c is a modifier gene that regulates faslpr-induced autoimmune disease. J Immunol. 2013;190:5436–45.PubMedCrossRefGoogle Scholar
  51. 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
  52. Ying H, Nakayama E, Robinson WH, Parnes JR. Structure of the mouse CD72 (Lyb-2) gene and its alternatively spliced transcripts. J Immunol. 1995;155:1637.PubMedPubMedCentralGoogle Scholar
  53. Zhou H, Qi AP, Li HY, Ma L, Xu JH, Xue F, Lu SH, Zhao QJ, Zhou ZP, Yang RC. CD72 gene expression in immune thrombocytopenia. Platelets. 2012;23:638–44.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Hsin-Jung Wu
    • 1
    Email author
  • Natarajan Muthusamy
    • 2
  • Subbarao Bondada
    • 3
  1. 1.Department of Microbiology and ImmunologyUniversity of ArizonaTucsonUSA
  2. 2.Division of Hematology, Department of Internal Medicine, Ohio State University Comprehensive Cancer CenterOhio State UniversityColumbusUSA
  3. 3.Department of Microbiology, Immunology and Molecular Genetics, Markey Cancer CenterUniversity of KentuckyLexingtonUSA