Adhesion-GPCRs pp 128-137 | Cite as

CD97 in Leukocyte Trafficking

  • Jörg Hamann
  • Henrike Veninga
  • Dorien M. de Groot
  • Lizette Visser
  • Claudia L. Hofstra
  • Paul P. Tak
  • Jon D. Laman
  • Annemieke M. Boots
  • Hans van Eenennaam
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 706)


CD97 is a member of the EGF-TM7 family of adhesion G protein-coupled receptors (GPCRs) broadly expressed on leukocytes. CD97 interacts with several cellular ligands via its N-terminal epidermal growth factor (EGF)-like domains. To understand the biological function of CD97, monoclonal antibodies (mAbs) specific for individual EGF domains have been applied in a variety of in vivo models in mice, which represent different aspects of innate and adaptive immunity. Targeting CD97 by mAbs inhibited the accumulation of neutrophilic granulocytes at sites of inflammation thereby affecting antibacterial host defense, inflammatory disorders and stem cell mobilization from bone marrow. Interestingly, targeting CD97 did not impact antigen-specific (adaptive response) models such as delayed type hypersensitivity (DTH) or experimental autoimmune encephalomyelitis (EAE). However, collagen-induced arthritis (CIA), a model for rheumatoid arthritis, was significantly ameliorated suggesting therapeutic value of CD97 targeting. CD97-deficient mice are essentially normal at steady state except for a mild granulocytosis, which increases under inflammatory conditions. Comparison of the consequences of antibody treatment and gene targeting implies that CD97 mAbs actively inhibit the innate response presumably at the level of granulocyte or macrophage recruitment to sites of inflammation. Based on the collected data, we propose that the CD97 mAbs either activate CD97-mediated signal transduction via a yet unknown mechanism or act by inducing CD97 internalization, making CD97 unavailable for binding to its ligands and thereby blocking recruitment of neutrophils and possibly macrophages.


Experimental Autoimmune Encephalomyelitis Delay Type Hypersensitivity Soluble CD97 CD97 mAbs Stem Cell Mobilization 
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  1. 1.
    Eichler W, Aust G, Hamann D. Characterization of an early activation-dependent antigen on lymphocytes defined by the monoclonal antibody BL-Ac(F2). Scand J Immunol 1994; 39:111–115.PubMedCrossRefGoogle Scholar
  2. 2.
    Kwakkenbos MJ, Kop EN, Stacey M et al. The EGF-TM7 family: a postgenomic view. Immunogenetics 2004; 55:655–666.PubMedCrossRefGoogle Scholar
  3. 3.
    Lagerström MC, Schiöth HB. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov 2008; 7:339–357.PubMedCrossRefGoogle Scholar
  4. 4.
    Yona S., Lin HH, Siu WO et al. Adhesion-GPCRs: emerging roles for novel receptors. Trends Biochem Sci 2008; 33:491–500.PubMedCrossRefGoogle Scholar
  5. 5.
    Kwakkenbos MJ, Matmati M, Madsen O et al. An unusual mode of concerted evolution of the EGF-TM7 receptor chimera EMR2. FASEB J 2006; 20:2582–2584.PubMedCrossRefGoogle Scholar
  6. 6.
    Kop EN, Matmati M, Pouwels W et al. Differential expression of CD97 on human lymphocyte subsets and limited effect of CD97 antibodies on allogeneic T-cell stimulation. Immunol Lett 2009; 123:160–168.PubMedCrossRefGoogle Scholar
  7. 7.
    Jaspars LH, Vos W, Aust G et al. Tissue distribution of the human CD97 EGF-TM7 receptor. Tissue Antigens 2001; 57:325–331.PubMedCrossRefGoogle Scholar
  8. 8.
    Aust G, Eichler W, Laue S et al. CD97: a dedifferentiation marker in human thyroid carcinomas. Cancer Res 1997; 57:1798–1806.PubMedGoogle Scholar
  9. 9.
    Aust G, Steinert M, Schütz A et al. CD97, but not its closely related EGF-TM7 family member EMR2, is expressed on gastric, pancreatic and esophageal carcinomas. Am J Clin Pathol 2002; 118:699–707.PubMedCrossRefGoogle Scholar
  10. 10.
    Aust G, Wandel E, Boltze C et al. Diversity of CD97 in smooth muscle cells. Cell Tissue Res 2006; 324:139–147.PubMedCrossRefGoogle Scholar
  11. 11.
    Hamann J, Eichler W, Hamann D et al. Expression cloning and chromosomal mapping of the leukocyte activation antigen CD97, anew seven-span transmembrane molecule of the secretion receptor superfamily with an unusual extracellular domain. J Immunol 1995; 155:1942–1950.PubMedGoogle Scholar
  12. 12.
    Gray JX, Haino M, Roth MJ et al. CD97 is a processed, seven-transmembrane, heterodimeric receptor associated with inflammation. J Immunol 1996; 157:5438–5447.PubMedGoogle Scholar
  13. 13.
    Qian YM, Haino M, Kelly K et al. Structural characterization of mouse CD97 and study of its specific interaction with murine decay-accelerating factor (DAF, CD55). Immunol 1999; 98:303–311.CrossRefGoogle Scholar
  14. 14.
    Hamann J, van Zeventer C, Bijl A et al. Molecular cloning and characterization of mouse CD97. Int Immunol 2000; 12:439–448.PubMedCrossRefGoogle Scholar
  15. 15.
    Hamann J, Vogel B, van Schijndel GMW et al. The seven-span transmembrane receptor CD97 has a cellular ligand (CD55, DAF). J Exp Med 1996; 184:1185–1189.PubMedCrossRefGoogle Scholar
  16. 16.
    Hamann J, Stortelers C, Kiss-Toth E et al. Characterization of the CD55 (DAF)-binding site on the seven-span transmembrane receptor CD97. Eur J Immunol 1998; 28:1701–1707.PubMedCrossRefGoogle Scholar
  17. 17.
    Lin HH, Stacey M, Saxby C et al. Molecular analysis of the epidermal growth factor-like short consensus repeat domain-mediated protein-protein interactions: dissection of the CD97-CD55 complex. J Biol Chem 2001; 276:24160–24169.PubMedCrossRefGoogle Scholar
  18. 18.
    Leemans JC, te Velde AA, Florquin S et al. The epidermal growth factor-seven transmembrane (EGF-TM7) receptor CD97 is required for neutrophil migration and host defense. J Immunol 2004; 172:1125–1131.PubMedGoogle Scholar
  19. 19.
    Stacey M, Chang GW, Davies JQ et al. The epidermal growth factor-like domains of human EMR2 receptor mediates cell attachment through chondroitin sulphate glycosaminoglycans. Blood 2003; 102:2916–2924.PubMedCrossRefGoogle Scholar
  20. 20.
    Kwakkenbos MJ, Pouwels W, Matmati M et al. Expression of the largest CD97 and EMR2 isoforms on leukocytes facilitates a specific interaction with chondroitin sulfate on B-cells. J Leukoc Biol 2005; 77:112–119.PubMedGoogle Scholar
  21. 21.
    Wang T, Ward Y, Tian LH et al. CD97, an adhesion receptor on inflammatory cells, stimulates angiogenesis through binding integrin counterreceptors on endothelial cells. Blood 2005; 105:2836–2844.PubMedCrossRefGoogle Scholar
  22. 22.
    Lin HH, Chang GW, Davies JQ et al. Autocatalytic cleavage of the EMR2 receptor occurs at a conserved G protein-coupled receptor proteolytic site motif. J Biol Chem 2004; 279:31823–31832.PubMedCrossRefGoogle Scholar
  23. 23.
    Van Pel M, Hagoort H, Kwakkenbos MJ et al. Differential role of CD97 in interleukin-8-induced and granulocyte-colony stimulating factor-induced hematopoietic stem and progenitor cell mobilization. Haematologica 2008; 93:601–604.PubMedCrossRefGoogle Scholar
  24. 24.
    Kop EN, Kwakkenbos MJ, Teske GJD et al. Identification of the epidermal growthfactor-TM7 receptor EMR2 and its ligand dermatan sulfate in rheumatoid synovial tissue. Arthritis Rheum 2005; 52:442–450.PubMedCrossRefGoogle Scholar
  25. 25.
    Kop EN, Adriaansen J, Smeets TJ et al. CD97 neutralisation increases resistance to collagen-induced arthritis in mice. Arthritis Res Ther 2006; 8:R155.PubMedCrossRefGoogle Scholar
  26. 26.
    De Groot DM, Vogel G, Dulos J et al. Therapeutic antibody targeting of CD97 in experimental arthritis; the role of antigen expression, shedding and internalization on the pharmacokinetics of anti-CD97 monoclonal antibody 1B2. J Immunol 2009; 183:4127–4134.PubMedCrossRefGoogle Scholar
  27. 27.
    Visser L, de Vos AF, Hamann J et al. Expression of the EGF-TM7 receptor CD97 and its ligand CD55 (DAF) in multiple sclerosis. J Neuroimmunol 2002; 132:156–163.PubMedCrossRefGoogle Scholar
  28. 28.
    Kataoka H, Sugahara K, Shimano K et al. FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T-cell infiltration. Cell Mol Immunol 2005; 2:439–448.PubMedGoogle Scholar
  29. 29.
    Ijima K, Murakami M, Okamoto H et al. Successful gene therapy via intraarticular injection of adenovirus vector containing CTLA4IgG in a murine model of type II collagen-induced arthritis. Hum Gene Ther 2001; 12:1063–1077.PubMedCrossRefGoogle Scholar
  30. 30.
    Veninga H, Becker S, Hoek RM et al. Analysis of CD97 expression and manipulation: antibody treatment but not gene targeting curtails granulocyte migration. J Immunol 2008; 181:6574–6583.PubMedGoogle Scholar
  31. 31.
    Wang T, Tian L, Haino M et al. Improved antibacterial host defense and altered peripheral granulocyte homeostasis in mice lacking the adhesion class G protein receptor CD97. Infect Immun 2007; 75:1144–1153.PubMedCrossRefGoogle Scholar
  32. 32.
    Davies JQ, Chang GW, Yona S et al. The role of receptor oligomerization in modulating the expression and function of leukocyte adhesion-G protein-coupled receptors. J Biol Chem 2007; 282:27343–27353.PubMedCrossRefGoogle Scholar
  33. 33.
    Hamann J, Wishaupt JO, van Lier RAW et al. Expression of the actvation antigen CD97 and its ligand in rheumatoid synovial tissue. Arthritis Rheum 1999; 42:650–658.PubMedCrossRefGoogle Scholar
  34. 34.
    Capasso M, Durrant LG, Stacey M et al. Costimulation via CD55 on human CD4+ T-cells mediated by CD97. J Immunol 2006; 177:1070–1077.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Jörg Hamann
    • 1
  • Henrike Veninga
  • Dorien M. de Groot
  • Lizette Visser
  • Claudia L. Hofstra
  • Paul P. Tak
  • Jon D. Laman
  • Annemieke M. Boots
  • Hans van Eenennaam
  1. 1.Department of Experimental Immunology, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands

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