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Gene Review

CD2  -  CD2 molecule

Homo sapiens

Synonyms: Erythrocyte receptor, LFA-2, LFA-3 receptor, Rosette receptor, SRBC, ...
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Disease relevance of CD2


Psychiatry related information on CD2


High impact information on CD2

  • CD2 ligation can mediate or enhance T-cell activation, suggesting that signals from CD2/LFA-3 adhesive interactions are integrated with signals from the T-cell antigen receptor during immunological recognition [10].
  • A myelogram disclosed a complete block of the subarachnoid space from levels T11 to L2 [11].
  • Using a two color imaging approach that allows tracking of single molecules relative to the CD2/LAT/Lck clusters, we demonstrate that these microdomains exclude and limit the free diffusion of molecules in the membrane but also can trap and immobilize specific proteins [12].
  • Interaction between CD2 and its counterreceptor, CD58 (LFA-3), on opposing cells optimizes immune recognition, facilitating contacts between helper T lymphocytes and antigen-presenting cells as well as between cytolytic effectors and target cells [13].
  • The mRNA for the Duffy blood group antigen, the erythrocyte receptor for the Plasmodium vivax malaria parasite, has recently been cloned and shown to encode a widely expressed chemokine receptor [14].

Chemical compound and disease context of CD2


Biological context of CD2

  • We have identified the binding sites for 16 monoclonal antibodies against CD2 by a rapid and generally applicable mutational analysis [20].
  • Such rapid binding kinetics have also been reported for the T cell adhesion molecule CD2 and may be necessary to accommodate-dynamic T cell-APC contacts and to facilitate scanning of APC for antigen [21].
  • A similar situation is seen in the region of the CD2 and LFA3 genes between mouse chromosome 3 and human chromosome 1p [22].
  • Human LFA-3 is genetically linked and is 21% identical in amino acid sequence to CD2, suggesting that this adhesive pair may have evolved from a single ancestral molecule [23].
  • To begin to define structure-function relationships in the extracellular segment of the transmembrane CD2 molecule, we have used a eukaryotic expression system and a CD2 cDNA to produce milligram amounts of recombinant soluble CD2 molecule that corresponds to the two extracellular segment exons [24].

Anatomical context of CD2

  • To understand the role of CD2 in T-cell adhesion and activation, it is essential to define its natural ligand [25].
  • We now report that CD2 binds to a cell-surface antigen known as lymphocyte function-associated antigen-3 (LFA-3) with high affinity, and can mediate adhesion of lymphoid cells via interaction with LFA-3 [25].
  • Our previous observation that purified CD2 inhibits rosetting of T lymphocytes with sheep erythrocytes and can be absorbed by sheep erythrocytes suggested it also might bind with detectable affinity to human cells [25].
  • Monoclonal antibodies to CD2 inhibit cytotoxic T-lymphocyte (CTL)-mediated killing by binding to the T lymphocyte and blocking adhesion to the target cell [25].
  • The majority of NK cells in unstimulated peripheral blood and the majority of NK clones express NKH1 and CD2 antigens but do not express CD3 antigen [26].

Associations of CD2 with chemical compounds

  • We have identified CD59, a glycoprotein with complement-inhibitory function, as a second physiological ligand for CD2 [27].
  • The CD58 binding site on human CD2 was recently shown by nuclear magnetic resonance structural data in conjunction with site-directed mutagenesis to be a highly charged surface area covering approximately 770A2 on the major AGFCC'C" face of the CD2 immunoglobulin-like (Ig-like) NH2-terminal domain [28].
  • NMR analysis shows that the Fyn but not the Lck tyrosine kinase SH3 domain competes with CD2BP2 GYF-domain binding to the same CD2 proline-rich sequence in vitro [29].
  • In addition, stimulation of neoplastic MCs through T11-3 and a second CD2 epitope resulted in histamine release [1].
  • AG490, a tyrosine kinase inhibitor affecting Jak proteins, inhibits CD2-mediated IFN-gamma mRNA expression, secretion, and nucleoprotein binding to the IFN-gamma STAT5 site in a dose-dependent fashion [30].

Physical interactions of CD2

  • Together with previous data, our studies suggest that CD2 on the effector interacts with LFA-3 as its ligand on targets [31].
  • In mice, the CD48 molecule can bind to CD2 [32].
  • These results directly show that CD2 binds CD59 and that subtle molecular changes occur upon binding [33].
  • CD5 coprecipitates with CD2 in CD3-deficient cells and, conversely, coprecipitates with CD3 in cells devoid of CD2 [34].
  • This costimulatory effect of ICAM-2 was dependent on its coimmobilization with mAb directed at the CD3/TCR complex but not those directed at CD2 or CD28 [35].

Enzymatic interactions of CD2


Regulatory relationships of CD2

  • Antibodies to CD59 inhibit CD2-dependent T cell activation in murine T cell hybridomas expressing human CD2 [27].
  • 125I-CD2 binding to E is inhibited by LFA-3 mAb; reciprocally, binding of LFA-3 mAb to human E is inhibited by pretreatment with purified CD2 [40].
  • The mutated CD2 molecules were functional in that pairs of anti-CD2 mAb that continued to bind were able to stimulate IL-2 production by the hybridomas [41].
  • It has been found that both TNF-alpha synthesis and secretion were induced after incubation of purified T lymphocytes with the appropriate mitogenic combination of antibodies specific for two different epitopes on the CD2 molecule [42].
  • Preincubation of Jurkat E6.1 cells with cholera toxin or with the protein tyrosine kinase inhibitor herbimycin A reduced the gal-1 induced calcium response whereas the increase in [Ca(2+)](i)stimulated by CD2 or CD3 monoclonal antibodies (mAbs) was completely inhibited [43].

Other interactions of CD2

  • These features explain CD2-CD58 dynamic binding, offering insights into interactions of related immunoglobulin superfamily receptors [13].
  • In addition to monoclonal antibodies against the CD3 (T3)-T-cell antigen receptor (CD3/Ti) complex, several other monoclonals directed towards distinct cell surface structures on human (CD2 (T11) and Tp44) and murine (Thy-1, TAP, and Ly-6) T lymphocytes are capable of activating T cells [44].
  • Certain combinations of monoclonal antibodies to CD2 epitopes trigger proliferation of peripheral blood T lymphocytes, cytotoxic effector function and expression of IL-2 receptors by thymocytes, resulting in thymocyte proliferation in the presence of exogenous IL-2 (ref. 11) [25].
  • Using surface plasmon resonance, we showed that purified soluble mCD48 bound m2B4 with a six- to ninefold higher affinity (Kd approximately 16 microM at 37 degreesC) than its other ligand, CD2 [45].
  • 2B4 is a cell surface glycoprotein related to CD2 and implicated in the regulation of natural killer and T lymphocyte function [45].

Analytical, diagnostic and therapeutic context of CD2


  1. Expression, epitope analysis, and functional role of the LFA-2 antigen detectable on neoplastic mast cells. Schernthaner, G.H., Jordan, J.H., Ghannadan, M., Agis, H., Bevec, D., Nuñez, R., Escribano, L., Majdic, O., Willheim, M., Worda, C., Printz, D., Fritsch, G., Lechner, K., Valent, P. Blood (2001) [Pubmed]
  2. Interleukin-2-dependent T-cell lines established from paroxysmal nocturnal hemoglobinuria patients. Nakakuma, H., Nagakura, S., Horikawa, K., Hidaka, M., Kawaguchi, T., Iwamoto, N., Sanada, I., Kagimoto, T., Takatsuki, K. Blood (1994) [Pubmed]
  3. Acute myeloid leukemia M4 with bone marrow eosinophilia (M4Eo) and inv(16)(p13q22) exhibits a specific immunophenotype with CD2 expression. Adriaansen, H.J., te Boekhorst, P.A., Hagemeijer, A.M., van der Schoot, C.E., Delwel, H.R., van Dongen, J.J. Blood (1993) [Pubmed]
  4. Differential expression of cell adhesion molecules CD54/CD11a and CD58/CD2 by human melanoma cells and functional role in their interaction with cytotoxic cells. Altomonte, M., Gloghini, A., Bertola, G., Gasparollo, A., Carbone, A., Ferrone, S., Maio, M. Cancer Res. (1993) [Pubmed]
  5. Loss of p27(Kip1) cooperates with cyclin E in T-cell lymphomagenesis. Geisen, C., Karsunky, H., Yücel, R., Möröy, T. Oncogene (2003) [Pubmed]
  6. Alteration of T and null lymphocyte frequencies in the peripheral blood of human opiate addicts: in vivo evidence for opiate receptor sites on T lymphocytes. McDonough, R.J., Madden, J.J., Falek, A., Shafer, D.A., Pline, M., Gordon, D., Bokos, P., Kuehnle, J.C., Mendelson, J. J. Immunol. (1980) [Pubmed]
  7. Phantom pain following limb amputation in a paraplegic. A case report. Catchlove, R.F. Psychotherapy and psychosomatics. (1983) [Pubmed]
  8. Personality, endocrine and immune changes after eight months in healthy individuals under normal daily stress. Biondi, M., Peronti, M., Pacitti, F., Pancheri, P., Pacifici, R., Altieri, I., Paris, L., Zuccaro, P. Psychotherapy and psychosomatics. (1994) [Pubmed]
  9. The effect of depression in an animal model on 5'-ectonucleotidase, antibody production, and tissue ascorbate stores. Blake-Mortimer, J.S., Winefield, A.H., Chalmers, A.H. The Journal of general psychology. (1998) [Pubmed]
  10. Role of lymphocyte adhesion receptors in transient interactions and cell locomotion. Dustin, M.L., Springer, T.A. Annu. Rev. Immunol. (1991) [Pubmed]
  11. Non-Hodgkin's lymphoma of the spinal cord. Routh, A. CA: a cancer journal for clinicians. (1980) [Pubmed]
  12. Single-molecule microscopy reveals plasma membrane microdomains created by protein-protein networks that exclude or trap signaling molecules in T cells. Douglass, A.D., Vale, R.D. Cell (2005) [Pubmed]
  13. Structure of a heterophilic adhesion complex between the human CD2 and CD58 (LFA-3) counterreceptors. Wang, J.H., Smolyar, A., Tan, K., Liu, J.H., Kim, M., Sun, Z.Y., Wagner, G., Reinherz, E.L. Cell (1999) [Pubmed]
  14. Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Tournamille, C., Colin, Y., Cartron, J.P., Le Van Kim, C. Nat. Genet. (1995) [Pubmed]
  15. Detection of hyperreactive T cells in multiple myeloma by multivalent cross-linking of the CD3/TCR complex. Massaia, M., Bianchi, A., Attisano, C., Peola, S., Redoglia, V., Dianzani, U., Pileri, A. Blood (1991) [Pubmed]
  16. Human cytomegalovirus proteinase: candidate glutamic acid identified as third member of putative active-site triad. Cox, G.A., Wakulchik, M., Sassmannshausen, L.M., Gibson, W., Villarreal, E.C. J. Virol. (1995) [Pubmed]
  17. Suramin affects human peripheral blood mononuclear cells in vitro: inhibition of T cell growth and modulation of cytokine secretion. Czernin, S., Gessl, A., Wilfing, A., Holter, W., Trieb, K., Waldhäusl, W., Vierhapper, H., Förster, O., Grubeck-Loebenstein, B. Int. Arch. Allergy Immunol. (1993) [Pubmed]
  18. Accessory receptors regulate coupling of the T-cell receptor complex to tyrosine kinase activation and mobilization of cytoplasmic calcium in T-lineage acute lymphoblastic leukemia. Ledbetter, J.A., Schieven, G.L., Kuebelbeck, V.M., Uckun, F.M. Blood (1991) [Pubmed]
  19. Anti-CD2 receptor antibodies activate the HIV long terminal repeat in T lymphocytes. Bressler, P., Pantaleo, G., Demaria, A., Fauci, A.S. J. Immunol. (1991) [Pubmed]
  20. Monoclonal antibody and ligand binding sites of the T cell erythrocyte receptor (CD2). Peterson, A., Seed, B. Nature (1987) [Pubmed]
  21. CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. van der Merwe, P.A., Bodian, D.L., Daenke, S., Linsley, P., Davis, S.J. J. Exp. Med. (1997) [Pubmed]
  22. Structure, expression, and genetic linkage of the mouse BCM1 (OX45 or Blast-1) antigen. Evidence for genetic duplication giving rise to the BCM1 region on mouse chromosome 1 and the CD2/LFA3 region on mouse chromosome 3. Wong, Y.W., Williams, A.F., Kingsmore, S.F., Seldin, M.F. J. Exp. Med. (1990) [Pubmed]
  23. Amino acid residues required for binding of lymphocyte function-associated antigen 3 (CD58) to its counter-receptor CD2. Osborn, L., Day, E.S., Miller, G.T., Karpusas, M., Tizard, R., Meuer, S.C., Hochman, P.S. J. Exp. Med. (1995) [Pubmed]
  24. Structural and binding analysis of a two domain extracellular CD2 molecule. Sayre, P.H., Hussey, R.E., Chang, H.C., Ciardelli, T.L., Reinherz, E.L. J. Exp. Med. (1989) [Pubmed]
  25. The T lymphocyte glycoprotein CD2 binds the cell surface ligand LFA-3. Selvaraj, P., Plunkett, M.L., Dustin, M., Sanders, M.E., Shaw, S., Springer, T.A. Nature (1987) [Pubmed]
  26. Characterization of functional surface structures on human natural killer cells. Ritz, J., Schmidt, R.E., Michon, J., Hercend, T., Schlossman, S.F. Adv. Immunol. (1988) [Pubmed]
  27. Overlapping but nonidentical binding sites on CD2 for CD58 and a second ligand CD59. Hahn, W.C., Menu, E., Bothwell, A.L., Sims, P.J., Bierer, B.E. Science (1992) [Pubmed]
  28. Interaction between human CD2 and CD58 involves the major beta sheet surface of each of their respective adhesion domains. Arulanandam, A.R., Kister, A., McGregor, M.J., Wyss, D.F., Wagner, G., Reinherz, E.L. J. Exp. Med. (1994) [Pubmed]
  29. Dynamic interaction of CD2 with the GYF and the SH3 domain of compartmentalized effector molecules. Freund, C., Kühne, R., Yang, H., Park, S., Reinherz, E.L., Wagner, G. EMBO J. (2002) [Pubmed]
  30. Enhancer role of STAT5 in CD2 activation of IFN-gamma gene expression. Gonsky, R., Deem, R.L., Bream, J., Young, H.A., Targan, S.R. J. Immunol. (2004) [Pubmed]
  31. Two antigen-independent adhesion pathways used by human cytotoxic T-cell clones. Shaw, S., Luce, G.E., Quinones, R., Gress, R.E., Springer, T.A., Sanders, M.E. Nature (1986) [Pubmed]
  32. Identification of the 2B4 molecule as a counter-receptor for CD48. Latchman, Y., McKay, P.F., Reiser, H. J. Immunol. (1998) [Pubmed]
  33. CD59 molecule: a second ligand for CD2 in T cell adhesion. Deckert, M., Kubar, J., Zoccola, D., Bernard-Pomier, G., Angelisova, P., Horejsi, V., Bernard, A. Eur. J. Immunol. (1992) [Pubmed]
  34. CD2 and CD3 associate independently with CD5 and differentially regulate signaling through CD5 in Jurkat T cells. Carmo, A.M., Castro, M.A., Arosa, F.A. J. Immunol. (1999) [Pubmed]
  35. Intercellular adhesion molecule-2, a second counter-receptor for CD11a/CD18 (leukocyte function-associated antigen-1), provides a costimulatory signal for T-cell receptor-initiated activation of human T cells. Damle, N.K., Klussman, K., Aruffo, A. J. Immunol. (1992) [Pubmed]
  36. Tyrosine phosphorylation and recruitment of ZAP-70 to the CD3-TCR complex are defective after CD2 stimulation. Hubert, P., Lang, V., Debré, P., Bismuth, G. J. Immunol. (1996) [Pubmed]
  37. Priming of CD2-induced p62Dok tyrosine phosphorylation by CD3 in Jurkat T cells. Harriague, J., Debré, P., Bismuth, G., Hubert, P. Eur. J. Immunol. (2000) [Pubmed]
  38. The lymphocyte-specific protein tyrosine kinase p56lck is hyperphosphorylated on serine and tyrosine residues within minutes after activation via T cell receptor or CD2. Danielian, S., Fagard, R., Alcover, A., Acuto, O., Fischer, S. Eur. J. Immunol. (1989) [Pubmed]
  39. Tyrosine phosphorylation and association with phospholipase C gamma-1 of the GAP-associated 62-kD protein after CD2 stimulation of Jurkat T cell. Hubert, P., Debré, P., Boumsell, L., Bismuth, G. J. Exp. Med. (1993) [Pubmed]
  40. Rosetting of activated human T lymphocytes with autologous erythrocytes. Definition of the receptor and ligand molecules as CD2 and lymphocyte function-associated antigen 3 (LFA-3). Plunkett, M.L., Sanders, M.E., Selvaraj, P., Dustin, M.L., Springer, T.A. J. Exp. Med. (1987) [Pubmed]
  41. Functional CD2 mutants unable to bind to, or be stimulated by, LFA-3. Wolff, H.L., Burakoff, S.J., Bierer, B.E. J. Immunol. (1990) [Pubmed]
  42. Regulation of tumor necrosis factor (TNF)-alpha synthesis and TNF receptors expression in T lymphocytes through the CD2 activation pathway. Santis, A.G., Campanero, M.R., Alonso, J.L., Sánchez-Madrid, F. Eur. J. Immunol. (1992) [Pubmed]
  43. Involvement of CD2 and CD3 in galectin-1 induced signaling in human Jurkat T-cells. Walzel, H., Blach, M., Hirabayashi, J., Kasai, K.I., Brock, J. Glycobiology (2000) [Pubmed]
  44. Thy-1-mediated T-cell activation requires co-expression of CD3/Ti complex. Gunter, K.C., Germain, R.N., Kroczek, R.A., Saito, T., Yokoyama, W.M., Chan, C., Weiss, A., Shevach, E.M. Nature (1987) [Pubmed]
  45. 2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48. Brown, M.H., Boles, K., van der Merwe, P.A., Kumar, V., Mathew, P.A., Barclay, A.N. J. Exp. Med. (1998) [Pubmed]
  46. Identification of a novel dimeric phosphoprotein (PP29/30) associated with signaling receptors in human T lymphocytes and natural killer cells. Schraven, B., Ratnofsky, S., Gaumont, Y., Lindegger, H., Kirchgessner, H., Bruyns, E., Moebius, U., Meuer, S.C. J. Exp. Med. (1994) [Pubmed]
  47. T-cell receptor-independent activation of clonal Th2 cells associated with chronic hypereosinophilia. Roufosse, F., Schandené, L., Sibille, C., Kennes, B., Efira, A., Cogan, E., Goldman, M. Blood (1999) [Pubmed]
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