Immunologic Research

, Volume 58, Issue 2–3, pp 179–185 | Cite as

Function of the tetraspanin molecule CD81 in B and T cells

  • Shoshana LevyEmail author


A case of a young girl diagnosed with an antibody deficiency syndrome serves to highlight the role of CD81 in B cell biology. Moreover, this case illustrates a fundamental function of the tetraspanin family, namely their association with partner proteins. Characterization of the patient’s B cells revealed lack of surface CD19 although both of her CD19 alleles were normal. Further analysis determined that her antibody deficiency syndrome was due to a mutation in the CD81 gene, which did not enable expression of CD19 on the surface of the patient’s B cells. Actually, the partnership of CD81 with CD19 and the dependency of CD19 for its trafficking to the cell surface expression were first documented in CD81-deficient mice. CD81 is a widely expressed protein, yet the mutation in the antibody-deficient patient impaired mostly her B cell function. CD81 is required for multiple normal physiological functions, which have been subverted by major human pathogens, such as hepatitis C virus. However, this review will focus on the function of CD81 in cells of the adaptive immune system. Specifically, it will highlight studies focusing on the different roles of CD81 in B and T cells and on its function in B–T cell interactions.


Tetraspanins Mutation Trafficking Glycosylation Antibody deficiency 


Conflict of interest

The author declares no conflict of interest.


  1. 1.
    Oren R, Takahashi S, Doss C, Levy R, Levy S. TAPA-1, the target of an antiproliferative antibody, defines a new family of transmembrane proteins. Mol Cell Biol. 1990;10(8):4007–15.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Takahashi S, Doss C, Levy S, Levy R. TAPA-1, the target of an antiproliferative antibody, is associated on the cell surface with the Leu-13 antigen. J Immunol (Baltimore, MD: 1950). 1990;145(7):2207–13.Google Scholar
  3. 3.
    Garcia-Espana A, Chung PJ, Sarkar IN, Stiner E, Sun TT, Desalle R. Appearance of new tetraspanin genes during vertebrate evolution. Genomics. 2008;91(4):326–34.CrossRefPubMedGoogle Scholar
  4. 4.
    Garcia-Espana A, Chung PJ, Zhao X, Lee A, Pellicer A, Yu J, Sun TT, Desalle R. Origin of the tetraspanin uroplakins and their co-evolution with associated proteins: implications for uroplakin structure and function. Mol Phylogenet Evol. 2006;41(2):355–67.CrossRefPubMedGoogle Scholar
  5. 5.
    Kitadokoro K, Bordo D, Galli G, Petracca R, Falugi F, Abrignani S, Grandi G, Bolognesi M. CD81 extracellular domain 3D structure: insight into the tetraspanin superfamily structural motifs. EMBO J. 2001;20(1–2):12–8.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Hemler ME. Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol. 2005;6(10):801–11.CrossRefPubMedGoogle Scholar
  7. 7.
    Levy S, Shoham T. The tetraspanin web modulates immune-signalling complexes. Nat Rev Immunol. 2005;5(2):136–48.CrossRefPubMedGoogle Scholar
  8. 8.
    Nydegger S, Khurana S, Krementsov DN, Foti M, Thali M. Mapping of tetraspanin-enriched microdomains that can function as gateways for HIV-1. J Cell Biol. 2006;173(5):795–807.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Bradbury LE, Kansas GS, Levy S, Evans RL, Tedder TF. 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(9):2841–50.PubMedGoogle Scholar
  10. 10.
    Fournier M, Peyrou M, Bourgoin L, Maeder C, Tchou I, Foti M. CD4 dimerization requires two cysteines in the cytoplasmic domain of the molecule and occurs in microdomains distinct from lipid rafts. Mol Immunol. 2010;47(16):2594–603.CrossRefPubMedGoogle Scholar
  11. 11.
    Imai T, Kakizaki M, Nishimura M, Yoshie O. Molecular analyses of the association of CD4 with two members of the transmembrane 4 superfamily, CD81 and CD82. J Immunol. 1995;155(3):1229–39.PubMedGoogle Scholar
  12. 12.
    Todd SC, Lipps SG, Crisa L, Salomon DR, Tsoukas CD. CD81 expressed on human thymocytes mediates integrin activation and interleukin 2-dependent proliferation. J Exp Med. 1996;184(5):2055–60.CrossRefPubMedGoogle Scholar
  13. 13.
    Charrin S, Manie S, Billard M, Ashman L, Gerlier D, Boucheix C, Rubinstein E. Multiple levels of interactions within the tetraspanin web. Biochem Biophys Res Commun. 2003;304(1):107–12.CrossRefPubMedGoogle Scholar
  14. 14.
    Berditchevski F, Tolias KF, Wong K, Carpenter CL, Hemler ME. A novel link between integrins, transmembrane-4 superfamily proteins (CD63 and CD81), and phosphatidylinositol 4-kinase. J Biol Chem. 1997;272(5):2595–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Mannion BA, Berditchevski F, Kraeft SK, Chen LB, Hemler ME. Transmembrane-4 superfamily proteins CD81 (TAPA-1), CD82, CD63, and CD53 specifically associated with integrin alpha 4 beta 1 (CD49d/CD29). J Immunol. 1996;157(5):2039–47.PubMedGoogle Scholar
  16. 16.
    Stipp CS, Kolesnikova TV, Hemler ME. EWI-2 is a major CD9 and CD81 partner and member of a novel Ig protein subfamily. J Biol Chem. 2001;276(44):40545–54.CrossRefPubMedGoogle Scholar
  17. 17.
    Charrin S, Le Naour F, Labas V, Billard M, Le Caer JP, Emile JF, Petit MA, Boucheix C, Rubinstein E. EWI-2 is a new component of the tetraspanin web in hepatocytes and lymphoid cells. Biochem J. 2003;373(Pt 2):409–21.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Sala-Valdes M, Ursa A, Charrin S, Rubinstein E, Hemler ME, Sanchez-Madrid F, Yanez-Mo M. EWI-2 and EWI-F link the tetraspanin web to the actin cytoskeleton through their direct association with ezrin–radixin–moesin proteins. J Biol Chem. 2006;281(28):19665–75.CrossRefPubMedGoogle Scholar
  19. 19.
    Coffey G, Rajapaksa R, Liu R, Sharpe O, Kuo C-C, Krauss S, Sagi Y, Davis R, Staudt L, Sharman J, Robinson W, Levy S. Engagement of CD81 induces ezrin tyrosine phosphorylation and its cellular redistribution with filamentous actin. J Cell Sci. 2009;122(Pt 17):3137–44.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Gordon-Alonso M, Sala-Valdes M, Rocha-Perugini V, Perez-Hernandez D, Lopez-Martin S, Ursa A, Alvarez S, Kolesnikova TV, Vazquez J, Sanchez-Madrid F, Yanez-Mo M. EWI-2 association with alpha-actinin regulates T cell immune synapses and HIV viral infection. J Immunol. 2012;189(2):689–700.CrossRefPubMedGoogle Scholar
  21. 21.
    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.CrossRefPubMedGoogle Scholar
  22. 22.
    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(5247):348–50.CrossRefPubMedGoogle Scholar
  23. 23.
    Mattila PK, Feest C, Depoil D, Treanor B, Montaner B, Otipoby KL, Carter R, Justement LB, Bruckbauer A, Batista FD. The actin and tetraspanin networks organize receptor nanoclusters to regulate B cell receptor-mediated signaling. Immunity. 2013;38(3):461–74.CrossRefPubMedGoogle Scholar
  24. 24.
    Matsumoto AK, Martin DR, Carter RH, Klickstein LB, Ahearn JM, Fearon DT. Functional dissection of the CD21/CD19/TAPA-1/Leu-13 complex of B lymphocytes. J Exp Med. 1993;178(4):1407–17.CrossRefPubMedGoogle Scholar
  25. 25.
    Maecker HT, Levy S. Normal lymphocyte development but delayed humoral immune response in CD81-null mice. J Exp Med. 1997;185(8):1505–10.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Miyazaki T, Muller U, Campbell KS. Normal development but differentially altered proliferative responses of lymphocytes in mice lacking CD81. EMBO J. 1997;16(14):4217–25.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Tsitsikov EN, Gutierrez-Ramos JC, Geha RS. Impaired CD19 expression and signaling, enhanced antibody response to type II T independent antigen and reduction of B-1 cells in CD81-deficient mice. Proc Natl Acad Sci USA. 1997;94(20):10844–9.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    van Zelm MC, Smet J, Adams B, Mascart F, Schandene L, Janssen F, Ferster A, Kuo CC, Levy S, van Dongen JJ, van der Burg M. CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. J Clin Invest. 2010;120(4):1265–74 PMCID: PMC2846042.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Shoham T, Rajapaksa R, Boucheix C, Rubinstein E, Poe JC, Tedder TF, Levy S. The tetraspanin CD81 regulates the expression of CD19 during B cell development in a postendoplasmic reticulum compartment. J Immunol. 2003;171(8):4062–72.CrossRefPubMedGoogle Scholar
  30. 30.
    Shoham T, Rajapaksa R, Kuo CC, Haimovich J, Levy S. Building of the tetraspanin web: distinct structural domains of CD81 function in different cellular compartments. Mol Cell Biol. 2006;26(4):1373–85 PMCID: 1367195.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Schick M, Nguyen V, Levy S. Anti-TAPA-1 antibodies induce protein tyrosine phosphorylation that is prevented by increasing intracellular thiol levels. J Immunol (Baltimore, MD: 1950). 1993;151(4):1918–25.Google Scholar
  32. 32.
    Cherukuri A, Shoham T, Sohn H, Levy S, Brooks S, Carter R, Pierce S. The tetraspanin CD81 is necessary for partitioning of coligated CD19/CD21-B cell antigen receptor complexes into signaling-active lipid rafts. J Immunol (Baltimore, MD: 1950). 2004;172(1):370–80.CrossRefGoogle Scholar
  33. 33.
    Sanyal M, Fernandez R, Levy S. Enhanced B cell activation in the absence of CD81. Int Immunol. 2009;21(11):1225–37.CrossRefPubMedGoogle Scholar
  34. 34.
    Schick MR, Levy S. The TAPA-1 molecule is associated on the surface of B cells with HLA-DR molecules. J Immunol. 1993;151(8):4090–7.PubMedGoogle Scholar
  35. 35.
    Rubinstein E, Le Naour F, Lagaudriere-Gesbert C, Billard M, Conjeaud H, Boucheix C. CD9, CD63, CD81, and CD82 are components of a surface tetraspan network connected to HLA-DR and VLA integrins. Eur J Immunol. 1996;26(11):2657–65.CrossRefPubMedGoogle Scholar
  36. 36.
    Angelisova P, Hilgert I, Horejsi V. Association of four antigens of the tetraspans family (CD37, CD53, TAPA-1, and R2/C33) with MHC class II glycoproteins. Immunogenetics. 1994;39:249–56.CrossRefPubMedGoogle Scholar
  37. 37.
    Szollosi J, Horejsi V, Bene L, Angelisova P, Damjanovich S. Supramolecular complexes of MHC class I, MHC class II, CD20, and teraspan molecules (CD53, CD81 and CD82) at the surface of a B cell line JY. J Immunol. 1996;157:2939–46.PubMedGoogle Scholar
  38. 38.
    Hoorn T, Paul P, Janssen L, Janssen H, Neefjes J. Dynamics within tetraspanin pairs affect MHC class II expression. J Cell Sci. 2012;125(Pt 2):328–39.CrossRefPubMedGoogle Scholar
  39. 39.
    Fukudome K, Furuse M, Imai T, Nishimura M, Takagi S, Hinuma Y, Yoshie O. Identification of membrane antigen C33 recognized by monoclonal antibodies inhibitory to human T-cell leukemia virus type 1 (HTLV-1)-induced syncytium formation: altered glycosylation of C33 antigen in HTLV-1-positive T cells. J Virol. 1992;66(3):1394–401 PMCID: PMC240862.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Gordon-Alonso M, Yanez-Mo M, Barreiro O, Alvarez S, Munoz-Fernandez MA, Valenzuela-Fernandez A, Sanchez-Madrid F. Tetraspanins CD9 and CD81 modulate HIV-1-induced membrane fusion. J Immunol. 2006;177(8):5129–37.CrossRefPubMedGoogle Scholar
  41. 41.
    Rubinstein E, Ziyyat A, Prenant M, Wrobel E, Wolf J-P, Levy S, Le Naour Fß, Boucheix C. Reduced fertility of female mice lacking CD81. Dev Biol. 2006;290(2):351–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Charrin S, Latil M, Soave S, Polesskaya A, Chretien F, Boucheix C, Rubinstein E. Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81. Nat Commun. 2013;4:1674.CrossRefPubMedGoogle Scholar
  43. 43.
    Potel J, Rassam P, Montpellier C, Kaestner L, Werkmeister E, Tews BA, Couturier C, Popescu CI, Baumert TF, Rubinstein E, Dubuisson J, Milhiet PE, Cocquerel L. EWI-2wint promotes CD81 clustering that abrogates Hepatitis C Virus entry. Cell Microbiol. 2013;15(7):1234–52.CrossRefPubMedGoogle Scholar
  44. 44.
    Boismenu R, Rhein M, Fischer WH, Havran WL. A role for CD81 in early T cell development. Science. 1996;271(5246):198–200.CrossRefPubMedGoogle Scholar
  45. 45.
    Maecker H, Todd S, Kim E, Levy S. Differential expression of murine CD81 highlighted by new anti-mouse CD81 monoclonal antibodies. Hybridoma. 2000;19(1):15–22.CrossRefPubMedGoogle Scholar
  46. 46.
    Witherden DA, Boismenu R, Havran WL. CD81 and CD28 costimulate T cells through distinct pathways. J Immunol. 2000;165(4):1902–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Sagi Y, Landrigan A, Levy R, Levy S. Complementary costimulation of human T-cell subpopulations by cluster of differentiation 28 (CD28) and CD81. Proc Natl Acad Sci USA. 2012;109(5):1613–8.PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Soldaini E, Wack A, D’Oro U, Nuti S, Ulivieri C, Baldari CT, Abrignani S. T cell costimulation by the hepatitis C virus envelope protein E2 binding to CD81 is mediated by Lck. Eur J Immunol. 2003;33(2):455–64.CrossRefPubMedGoogle Scholar
  49. 49.
    Crotta S, Stilla A, Wack A, D’Andrea A, Nuti S, D’Oro U, Mosca M, Filliponi F, Brunetto RM, Bonino F, Abrignani S, Valiante NM. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J Exp Med. 2002;195(1):35–41.PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Crotta S, Ronconi V, Ulivieri C, Baldari CT, Valiante NM, Abrignani S, Wack A. Cytoskeleton rearrangement induced by tetraspanin engagement modulates the activation of T and NK cells. Eur J Immunol. 2006;36(4):919–29.CrossRefPubMedGoogle Scholar
  51. 51.
    Tseng CT, Klimpel GR. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J Exp Med. 2002;195(1):43–9.PubMedCentralCrossRefPubMedGoogle Scholar
  52. 52.
    Clark KL, Zeng Z, Langford AL, Bowen SM, Todd SC. PGRL is a major CD81-associated protein on lymphocytes and distinguishes a new family of cell surface proteins. J Immunol. 2001;167(9):5115–21.CrossRefPubMedGoogle Scholar
  53. 53.
    Clark KL, Oelke A, Johnson ME, Eilert KD, Simpson PC, Todd SC. CD81 associates with 14-3-3 in a redox-regulated palmitoylation-dependent manner. J Biol Chem. 2004;279(19):19401–6.CrossRefPubMedGoogle Scholar
  54. 54.
    Mittelbrunn M, Yanez-Mo M, Sancho D, Ursa A, Sanchez-Madrid F. Cutting edge: dynamic redistribution of tetraspanin CD81 at the central zone of the immune synapse in both T lymphocytes and APC. J Immunol. 2002;169(12):6691–5.CrossRefPubMedGoogle Scholar
  55. 55.
    Rocha-Perugini V, Zamai M, Gonzalez-Granado JM, Barreiro O, Tejera E, Yanez-Mo M, Caiolfa VR, Sanchez-Madrid F. CD81 controls sustained T cell activation signaling and defines the maturation stages of cognate immunological synapses. Mol Cell Biol. 2013;33(18):3644–58 PMCID: PMC3753866.PubMedCentralCrossRefPubMedGoogle Scholar
  56. 56.
    Secrist H, Levy S, DeKruyff R, Umetsu D. Ligation of TAPA-1 (CD81) or major histocompatibility complex class II in co-cultures of human B and T lymphocytes enhances interleukin-4 synthesis by antigen-specific CD4 + T cells. Eur J Immunol. 1996;26(7):1435–42.CrossRefPubMedGoogle Scholar
  57. 57.
    Maecker H, Do M, Levy S. CD81 on B cells promotes interleukin 4 secretion and antibody production during T helper type 2 immune responses. Proc Natl Acad Sci USA. 1998;95(5):2458–62.PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    Deng J, Yeung V, Tsitoura D, DeKruyff R, Umetsu D, Levy S. Allergen-induced airway hyperreactivity is diminished in CD81-deficient mice. J Immunol (Baltimore, MD: 1950). 2000;165(9):5054–61.CrossRefGoogle Scholar
  59. 59.
    Deng J, Dekruyff R, Freeman G, Umetsu D, Levy S. Critical role of CD81 in cognate T–B cell interactions leading to Th2 responses. Int Immunol. 2002;14(5):513–23.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Division of Oncology, Department of MedicineStanford University School of MedicineStanfordUSA

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