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Gene Review

CD58  -  CD58 molecule

Homo sapiens

Synonyms: Ag3, LFA-3, LFA3, Lymphocyte function-associated antigen 3, Surface glycoprotein LFA-3, ...
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Disease relevance of CD58

  • These results suggest that membrane-bound CD54 and CD58 and cCD54 play a role in host-tumor interactions in patients with malignant melanoma and may account for the relationship between CD54 expression in primary lesions and the clinical course of disease [1].
  • In biopsies from CIDP and vasculitic neuropathy patients, but not in those from healthy controls, Schwann cells expressed the adhesion/T-cell stimulatory molecule CD58 (LFA-3) [2].
  • The 2.5-kb CD58 promoter sequence displayed functional activity in transient transfection assays in the hepatocellular carcinoma cell line HepG2 [3].
  • Furthermore, cells from patients with common variable immunodeficiency produced IgE in response to IL-4 plus CD40 mAb but not to IL-4 plus CD58 mAb [4].
  • In paired specimens of ascites and peripheral blood, the proportion of lineage-negative HLA-DR+ cells that coexpressed CD86 or CD58 was significantly lower in ascites than in peripheral blood, whereas a higher proportion of lineage-negative HLA-DR+ cells in ascites expressed CD4 [5].

High impact information on CD58

  • 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 [6].
  • High levels of MHC class-I and -II products and several adhesins, such as ICAM-1 and LFA-3, likely contribute to these functions [7].
  • A model for the role of LFA-3 lateral diffusion in adhesion is presented, based on the lateral diffusion of different LFA-3 forms in glass supported planar membranes [6].
  • The CD2 T lymphocyte-surface glycoprotein serves to mediate adhesion between T lymphocytes and their cognate cellular partners which express the specific ligand LFA-3 [8].
  • The antigen-specific response of T hybridoma cells expressing human CD2trans- protein was enhanced up to 400% when the human LFA-3 ligand was introduced into the I-Ad expressing murine antigen-presenting cells [8].

Chemical compound and disease context of CD58

  • The reduced expression of HLA-class II antigens (DQ and DP) and some intercellular adhesion molecules (CD11b, CD54 and CD58) was found on monocytes after phagocytosis of bacteria (S. aureus, E. coli, P. aeruginosa, S. enteritidis) but not of latex particles [9].
  • This domain is resistant to proteolysis, even though it lacks any intrachain disulfides and, like the entire extracellular segment protein expressed in a baculovirus system, binds to its cellular ligand, LFA-3 [10].
  • IL-4 induces LFA-1 and LFA-3 expression on Burkitt's lymphoma cell lines. Requirement of additional activation by phorbol myristate acetate for induction of homotypic cell adhesions [11].
  • In contrast, we did not detect expression of the alpha 1 beta 1 integrin on any autologous lung adenocarcinoma cells, and they showed on average a 50% reduction in labeling relative intensity units for the integrin common chain marker beta 1, the specific integrins alpha 3 beta 1, alpha 5 beta 1, and alpha 6 beta 1, and ICAM-1, and LFA-3 [12].

Biological context of CD58

  • With two complementary approaches, it was demonstrated that the binding sites on CD2 for CD58 and CD59 are overlapping but nonidentical [13].
  • Mutagenesis of all residues in the vicinity of the glycan suggests that the glycan is not a component of the CD2-CD58 interface; rather, the carbohydrate stabilizes the protein fold by counterbalancing an unfavorable clustering of five positive charges centered about lysine-61 of CD2 [14].
  • CONCLUSIONS: CD58 is expressed by polarized IECs in a topologically restricted manner at the region of T-cell contact and can function as a costimulatory molecule in HLA class II-mediated antigen presentation [15].
  • The data support the notion that downregulation of CD54 and CD58 correlates with enhanced numbers of blasts in circulation and unsusceptibility to killing by autologous cytotoxic lymphocytes [16].
  • Here, we show that Ddull cells have an intermediate phenotype for antigens such as CD31, CD621, CD58, and CD95 that are differentially expressed on unprimed versus primed T cells [17].

Anatomical context of CD58


Associations of CD58 with chemical compounds

  • 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 [22].
  • Incubation of JY cells with immobilized anti-CD58 Abs results in extensive tyrosine phosphorylation and in secretion of TNF-alpha [23].
  • We have recently demonstrated that the interaction of CD2 with CD58 is dynamic: TCR stimulation or treatment with the phorbol ester PMA rapidly up-regulates CD2 ligand avidity, and this regulation requires the carboxyl-terminal asparagine residue of the CD2 cytoplasmic domain [24].
  • Alanine mutations at D31, D32 and K34 on the C strand and K43 and R48 on the C' strand reduce affinity for CD58 by 47-127-fold as measured by isothermal titration calorimetry [25].
  • CD80, CD58, rIL-12 and rIFN-alpha all had efficacious and independent costimulatory activities on the IL-10 production, while PGE2 was inhibitory [26].

Physical interactions of CD58

  • Costimulation by B7-1 and LFA-3 targets distinct nuclear factors that bind to the interleukin-2 promoter: B7-1 negatively regulates LFA-3-induced NF-AT DNA binding [27].
  • We have previously demonstrated that a mutation at amino acid 51 of CD2 results in loss of binding to LFA-3 [28].
  • LFA-3 costimulation only moderately enhances AP-1 DNA-binding activity and does not influence the NF-kappa B activity induced by TCR engagement, whereas B7 costimulation induces large amounts of NF-kappa B and AP-1 activity in T helper cells [29].

Regulatory relationships of CD58

  • This selectivity may contribute to regulation of the levels of IL-2 induced by LFA-3 and B7-1 costimulation and favor autocrine and paracrine T-cell responses, respectively [27].
  • To investigate whether cAMP may play a role in ligand-triggered CD2-mediated signal transduction, we have studied the ability of purified LFA-3 and anti-CD2 mAb to induce changes in intracellular cAMP content in murine Ag-specific T cell hybridomas that stably express wild-type and mutated human CD2 molecules [30].
  • Finally, the ability of CD59 to enhance CD58-dependent T cell responses was shown to be dependent on N-glycosylation of CD59 at amino acid Asn18 [31].
  • Both LFA-3 costimulation and B7-1 costimulation induced the AP-1 and NF-kappaB nuclear factors [27].
  • The presence of B7 induced a more vigorous and prolonged proliferative T cell response compared with LFA-3 costimulation [32].

Other interactions of CD58

  • 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 [33].
  • These observations suggest that direct interactions between CD2 and both CD58 and CD59 contribute to T cell activation and adhesion [13].
  • Given the importance of the CD2-CD48 interaction in the murine system and CD2-CD58 interaction in humans, it would appear that there has been a divergence of functional CD2 ligands during the evolution of humans and mice [34].
  • RESULTS: CD58, but not CD80 or CD86, was observed to be expressed constitutively on both native IECs and in the IEC lines T84 and HT-29 [15].
  • Antibodies against CD58, but not CD80 or CD86, inhibited the stimulation of CD4(+) T-cell proliferation mediated by IECs [15].

Analytical, diagnostic and therapeutic context of CD58

  • Although CD58 ligation alone was unable to induce epsilon germ-line transcription, in concert with IL-4-stimulated epsilon germ-line transcription it induced the appearance of productive epsilon transcripts and IgE production [4].
  • In ANLL, higher expression of CD58 was independently associated with higher CR rate (p = 0.04), longer overall survival (p = 0.02), and longer disease-free survival (p = 0.007) [35].
  • Previous gene mapping studies in human and mouse have suggested that CD2, CD48, and CD58 arose by gene duplication [36].
  • Out of the total nucleated cells, 23 +/-10.4% of cells in CB cell culture and 25 +/-5% of cells in the BM cell culture acquired DC characteristic phenotypes, which were marked expressions of CD1a, HLA-DR, co-stimulatory molecules such as CD80, CD40, and adhesion molecule such as CD58 [37].
  • Expression of glycosyl-phosphatidylinositol-linked glycoproteins in blood cells from paroxysmal nocturnal haemoglobinuria patients: a flow cytometry study using CD55, CD58 and CD59 monoclonal antibodies [38].


  1. 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]
  2. Expression of accessory molecules for T-cell activation in peripheral nerve of patients with CIDP and vasculitic neuropathy. Van Rhijn, I., Van den Berg, L.H., Bosboom, W.M., Otten, H.G., Logtenberg, T. Brain (2000) [Pubmed]
  3. Gene structure, promoter characterization, and basis for alternative mRNA splicing of the human CD58 gene. Wallich, R., Brenner, C., Brand, Y., Roux, M., Reister, M., Meuer, S. J. Immunol. (1998) [Pubmed]
  4. CD58 (LFA-3) stimulation provides a signal for human isotype switching and IgE production distinct from CD40. Diaz-Sanchez, D., Chegini, S., Zhang, K., Saxon, A. J. Immunol. (1994) [Pubmed]
  5. Lineage-negative human leukocyte antigen-DR+ cells with the phenotype of undifferentiated dendritic cells in patients with carcinoma of the abdomen and pelvis. Melichar, B., Savary, C., Kudelka, A.P., Verschraegen, C., Kavanagh, J.J., Edwards, C.L., Platsoucas, C.D., Freedman, R.S. Clin. Cancer Res. (1998) [Pubmed]
  6. Role of lymphocyte adhesion receptors in transient interactions and cell locomotion. Dustin, M.L., Springer, T.A. Annu. Rev. Immunol. (1991) [Pubmed]
  7. The dendritic cell system and its role in immunogenicity. Steinman, R.M. Annu. Rev. Immunol. (1991) [Pubmed]
  8. CD2-mediated adhesion facilitates T lymphocyte antigen recognition function. Moingeon, P., Chang, H.C., Wallner, B.P., Stebbins, C., Frey, A.Z., Reinherz, E.L. Nature (1989) [Pubmed]
  9. The reduced expression of HLA-class II antigens and adhesion molecules on monocyte surface after phagocytosis of bacteria. Baran, J., Pryjma, J. Arch. Immunol. Ther. Exp. (Warsz.) (1994) [Pubmed]
  10. The structural biology of CD2. Moingeon, P., Chang, H.C., Sayre, P.H., Clayton, L.K., Alcover, A., Gardner, P., Reinherz, E.L. Immunol. Rev. (1989) [Pubmed]
  11. IL-4 induces LFA-1 and LFA-3 expression on Burkitt's lymphoma cell lines. Requirement of additional activation by phorbol myristate acetate for induction of homotypic cell adhesions. Rousset, F., Billaud, M., Blanchard, D., Figdor, C., Lenoir, G.M., Spits, H., De Vries, J.E. J. Immunol. (1989) [Pubmed]
  12. Loss of alpha 1 beta 1 and reduced expression of other beta 1 integrins and CAM in lung adenocarcinoma compared with pneumocytes. Roussel, E., Gingras, M.C., Ro, J.Y., Branch, C., Roth, J.A. Journal of surgical oncology. (1994) [Pubmed]
  13. 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]
  14. Conformation and function of the N-linked glycan in the adhesion domain of human CD2. Wyss, D.F., Choi, J.S., Li, J., Knoppers, M.H., Willis, K.J., Arulanandam, A.R., Smolyar, A., Reinherz, E.L., Wagner, G. Science (1995) [Pubmed]
  15. Polarized expression and function of the costimulatory molecule CD58 on human intestinal epithelial cells. Framson, P.E., Cho, D.H., Lee, L.Y., Hershberg, R.M. Gastroenterology (1999) [Pubmed]
  16. Adhesion molecules on freshly recovered T leukemias promote tumor-directed lympholysis. Schirren, C.A., Völpel, H., Meuer, S.C. Blood (1992) [Pubmed]
  17. Heterogeneity of the human CD4+ T-cell population: two distinct CD4+ T-cell subsets characterized by coexpression of CD45RA and CD45RO isoforms. Hamann, D., Baars, P.A., Hooibrink, B., van Lier, R.W. Blood (1996) [Pubmed]
  18. 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]
  19. Mutational analysis of the CD2/CD58 interaction: the binding site for CD58 lies on one face of the first domain of human CD2. Somoza, C., Driscoll, P.C., Cyster, J.G., Williams, A.F. J. Exp. Med. (1993) [Pubmed]
  20. The CD58 (LFA-3) binding site is a localized and highly charged surface area on the AGFCC'C" face of the human CD2 adhesion domain. Arulanandam, A.R., Withka, J.M., Wyss, D.F., Wagner, G., Kister, A., Pallai, P., Recny, M.A., Reinherz, E.L. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  21. Aplastic anemia and paroxysmal nocturnal hemoglobinuria: search for a pathogenetic link. Griscelli-Bennaceur, A., Gluckman, E., Scrobohaci, M.L., Jonveaux, P., Vu, T., Bazarbachi, A., Carosella, E.D., Sigaux, F., Socié, G. Blood (1995) [Pubmed]
  22. 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]
  23. The glycosylphosphatidylinositol-anchored form and the transmembrane form of CD58 associate with protein kinases. Itzhaky, D., Raz, N., Hollander, N. J. Immunol. (1998) [Pubmed]
  24. Signal transduction pathways involved in T cell receptor-induced regulation of CD2 avidity for CD58. Hahn, W.C., Burakoff, S.J., Bierer, B.E. J. Immunol. (1993) [Pubmed]
  25. Molecular dissection of the CD2-CD58 counter-receptor interface identifies CD2 Tyr86 and CD58 Lys34 residues as the functional "hot spot". Kim, M., Sun, Z.Y., Byron, O., Campbell, G., Wagner, G., Wang, J., Reinherz, E.L. J. Mol. Biol. (2001) [Pubmed]
  26. Regulation of the IL-10 production by human T cells. Rafiq, K., Charitidou, L., Bullens, D.M., Kasran, A., Lorré, K., Ceuppens, J., van Gool, S.W. Scand. J. Immunol. (2001) [Pubmed]
  27. Costimulation by B7-1 and LFA-3 targets distinct nuclear factors that bind to the interleukin-2 promoter: B7-1 negatively regulates LFA-3-induced NF-AT DNA binding. Parra, E., Varga, M., Hedlund, G., Kalland, T., Dohlsten, M. Mol. Cell. Biol. (1997) [Pubmed]
  28. 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]
  29. T cell activation pathways: B7, LFA-3, and ICAM-1 shape unique T cell profiles. Wingren, A.G., Parra, E., Varga, M., Kalland, T., Sjögren, H.O., Hedlund, G., Dohlsten, M. Crit. Rev. Immunol. (1995) [Pubmed]
  30. Interaction of CD2 with its ligand lymphocyte function-associated antigen-3 induces adenosine 3',5'-cyclic monophosphate production in T lymphocytes. Hahn, W.C., Rosenstein, Y., Burakoff, S.J., Bierer, B.E. J. Immunol. (1991) [Pubmed]
  31. CD59 costimulation of T cell activation. CD58 dependence and requirement for glycosylation. Menu, E., Tsai, B.C., Bothwell, A.L., Sims, P.J., Bierer, B.E. J. Immunol. (1994) [Pubmed]
  32. Costimulation of human CD4+ T lymphocytes with B7 and lymphocyte function-associated antigen-3 results in distinct cell activation profiles. Parra, E., Wingren, A.G., Hedlund, G., Björklund, M., Sjögren, H.O., Kalland, T., Sansom, D., Dohlsten, M. J. Immunol. (1994) [Pubmed]
  33. 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]
  34. A soluble multimeric recombinant CD2 protein identifies CD48 as a low affinity ligand for human CD2: divergence of CD2 ligands during the evolution of humans and mice. Arulanandam, A.R., Moingeon, P., Concino, M.F., Recny, M.A., Kato, K., Yagita, H., Koyasu, S., Reinherz, E.L. J. Exp. Med. (1993) [Pubmed]
  35. Expression of surface adhesion molecules CD54 (ICAM-1) and CD58 (LFA-3) in adult acute leukemia: relationship with initial characteristics and prognosis. Archimbaud, E., Thomas, X., Campos, L., Magaud, J.P., Doré, J.F., Fiere, D. Leukemia (1992) [Pubmed]
  36. Physical and genetic linkage of the genes encoding Ly-9 and CD48 on mouse and human chromosomes 1. Kingsmore, S.F., Souryal, C.A., Watson, M.L., Patel, D.D., Seldin, M.F. Immunogenetics (1995) [Pubmed]
  37. Generation of functional and mature dendritic cells from cord blood and bone marrow CD34+ cells by two-step culture combined with calcium ionophore treatment. Liu, A., Takahashi, M., Narita, M., Zheng, Z., Kanazawa, N., Abe, T., Nikkuni, K., Furukawa, T., Toba, K., Fuse, I., Aizawa, Y. J. Immunol. Methods (2002) [Pubmed]
  38. Expression of glycosyl-phosphatidylinositol-linked glycoproteins in blood cells from paroxysmal nocturnal haemoglobinuria patients: a flow cytometry study using CD55, CD58 and CD59 monoclonal antibodies. Navenot, J.M., Bernard, D., Harousseau, J.L., Muller, J.Y., Blanchard, D. Leuk. Lymphoma (1996) [Pubmed]
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