Adhesion-GPCRs pp 149-156 | Cite as

F4/80: The Macrophage-Specific Adhesion-GPCR and its Role in Immunoregulation

  • Hsi-Hsien Lin
  • Martin Stacey
  • Joan Stein-Streilein
  • Siamon Gordon
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 706)


Asamacrophage-restrictedreagent, the generation and application of the F4/80 mAb has greatly benefited the phenotypic characterization of mouse tissue macrophages for three decades. Following the molecular identification of the F4/80 antigen as an EGF-TM7 member of the adhesion-GPCR family, great interest was ignited to understand its cell type-specific expression pattern as well as its functional role in macrophage biology. Recent studies have shown that the F4/80 gene is regulated by a novel set of transcription factors that recognized a unique promoter sequence. Gene targeting experiments have produced two F4/80 knock out animal models and showed that F4/80 isnotrequired for normal macrophage development. Nevertheless, the F4/80 receptor was found to be necessary for the induction of efferent CD8+ regulatory T cells responsible for peripheral immune tolerance. The identification of cellular ligands for F4/80 and delineation of its signaling pathway remain elusive but are critical to understand the in vivo role of this macrophage-specific adhesion-GPCR.


Treg Cell Cell Surface Glycoprotein Leukoc Biol Cellular Ligand Gene Target Experiment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Taylor PR, Martinez-Pomares L, Stacey M et al. Macrophage receptors and immune recognition. Annu Rev Immunol 2005; 23:901–944.PubMedCrossRefGoogle Scholar
  2. 2.
    Martinez-Pomares L, Platt N, McKnight AJ et al. Macrophage membrane molecules: markers of tissue differentiation and heterogeneity. Immunobiology 1996; 195(4-5):407–416.PubMedGoogle Scholar
  3. 3.
    McKnight AJ, Gordon S. Membrane molecules as differentiation antigens of murine macrophages. Adv Immunol 1998; 68:271–314.PubMedCrossRefGoogle Scholar
  4. 4.
    Austyn JM, Gordon S. F4/80, a monoclonal antibody directed specifically against the mouse macrophage. Eur J Immunol 1981; 11(10):805–815.PubMedCrossRefGoogle Scholar
  5. 5.
    Starkey PM, Turley L, Gordon S. The mouse macrophage-specific glycoprotein defined by monoclonal antibody F4/80: characterization, biosynthesis and demonstration of a rat analogue. Immunology 1987; 60(1):117–122.PubMedGoogle Scholar
  6. 6.
    Lin HH, Stubbs LJ, Mucenski ML. Identification and characterization of a seven transmembrane hormone receptor using differential display. Genomics 1997; 41(3):301–308.PubMedCrossRefGoogle Scholar
  7. 7.
    McKnight AJ, Macfarlane AJ, Dri P et al. Molecular cloning of F4/80, a murine macrophage-restricted cell surface glycoprotein with homology to the G-protein-linked transmembrane 7 hormone receptor family. J Biol Chem 1996;271(1):486–489.PubMedCrossRefGoogle Scholar
  8. 8.
    Lin HH, Faunce DE, Stacey M et al. The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T-cells in peripheral tolerance. J Exp Med 2005; 201(10):1615–1625.PubMedCrossRefGoogle Scholar
  9. 9.
    Schaller E, Macfarlane AJ, Rupec RA et al. Inactivation of the F4/80 glycoprotein in the mouse germ line. Mol Cell Biol 2002; 22(22):8035–8043.PubMedCrossRefGoogle Scholar
  10. 10.
    van den Berg TK, Kraal G. A function for the macrophage F4/80 molecule in tolerance induction. Trends Immunol 2005; 26(10):506–509.PubMedCrossRefGoogle Scholar
  11. 11.
    Gordon S. The Legacy of cell fusion. Oxford; New York: Oxford University Press; 1994.Google Scholar
  12. 12.
    Ezekowitz RA, Austyn J, Stahl PD et al. Surface properties of bacillus Calmette-Guerin-activated mouse macrophages. Reduced expression of mannose-specific endocytosis, Fc receptors and antigen F4/80 accompanies induction of Ia. J Exp Med 1981; 154(1):60–76.PubMedCrossRefGoogle Scholar
  13. 13.
    Hirsch S, Austyn JM, Gordon S. Expression of the macrophage-specific antigen F4/80 during differentiation of mouse bone marrow cells in culture. J Exp Med 1981; 154(3):713–725.PubMedCrossRefGoogle Scholar
  14. 14.
    McGarry MP, Stewart CC. Murine eosinophil granulocytes bind the murine macrophage-monocyte specific monoclonal antibody F4/80. J Leukoc Biol 1991; 50(5):471–478.PubMedGoogle Scholar
  15. 15.
    Hume DA, Robinson AP, MacPherson GG et al. The mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80. Relationship between macrophages, Langerhans cells, reticular cells and dendritic cells in lymphoid and hematopoietic organs. J Exp Med 1983; 158(5):1522–1536.PubMedCrossRefGoogle Scholar
  16. 16.
    McKnight AJ, Gordon S. EGF-TM7: anovel subfamily of seven-transmembrane-region leukocyte cell-surface molecules. Immunol Today 1996; 17(6):283–287.PubMedCrossRefGoogle Scholar
  17. 17.
    McKnight AJ, Gordon S. The EGF-TM7 family: unusual structures at the leukocyte surface. J Leukoc Biol 1998; 63(3):271–280.PubMedGoogle Scholar
  18. 18.
    Lee SH, Starkey PM, Gordon S. Quantitative analysis of total macrophage content in adult mouse tissues. Immunochemical studies with monoclonal antibody F4/80. J Exp Med 1985; 161(3):475–489.PubMedCrossRefGoogle Scholar
  19. 19.
    Gordon S, Lawson L, Rabinowitz S et al. Antigen markers of macrophage differentiation in murine tissues. Curr Top Microbiol Immunol 1992; 181:1–37.PubMedGoogle Scholar
  20. 20.
    Ezekowitz RA, Gordon S. Down-regulation of mannosyl receptor-mediated endocytosis and antigen F4/80 in bacillus Calmette-Guerin-activated mouse macrophages. Role of T-lymphocytes and lymphokines. J Exp Med 1982; 155(6):1623–1637.PubMedCrossRefGoogle Scholar
  21. 21.
    Ezekowitz RA, Gordon S. Surface properties of activated macrophages: sensitized lymphocytes, specific antigen and lymphokines reduce expression of antigen F4/80 and FC and mannose/fucosyl receptors, but induce Ia. Adv Exp Med Biol 1982; 155:401–407.PubMedGoogle Scholar
  22. 22.
    Haidl ID, Jefferies WA. Themacrophage cell surface glycoprotein F4/80 is ahighly glycosylated proteoglycan. Eur J Immunol 1996; 26(5):1139–1146.PubMedCrossRefGoogle Scholar
  23. 23.
    Stacey M, Lin HH, Gordon S et al. LNB-TM7, a group of seven-transmembrane proteins related to family-B G-protein-coupled receptors. Trends Biochem Sci 2000; 25(6):284–289.PubMedCrossRefGoogle Scholar
  24. 24.
    Kwakkenbos MJ, Kop EN, Stacey M et al. The EGF-TM7 family: a postgenomic view. Immunogenetics 2004; 55(10):655–666.PubMedCrossRefGoogle Scholar
  25. 25.
    Baud V, Chissoe SL, Viegas-Pequignot E et al. EMR1, an unusual member in the family of hormone receptors with seven transmembrane segments. Genomics 1995; 26(2):334–344.PubMedCrossRefGoogle Scholar
  26. 26.
    Hamann J, Koning N, Pouwels W et al. EMR1, the human homolog of F4/80, is an eosinophil-specific receptor. Eur J Immunol 2007; 37(10):2797–2802.PubMedCrossRefGoogle Scholar
  27. 27.
    Yona S, Lin HH, Siu WO et al. Adhesion-GPCRs: emerging roles for novel receptors. Trends Biochem Sci 2008; 33(10):491–500.PubMedCrossRefGoogle Scholar
  28. 28.
    McKnight AJ, Macfarlane AJ, Seldin MF et al. Chromosome mapping of the Emrl gene. Mamm Genome 1997; 8(12):946.PubMedCrossRefGoogle Scholar
  29. 29.
    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(14):2582–2584.PubMedCrossRefGoogle Scholar
  30. 30.
    Stacey M, Chang GW, Sanos SL et al. EMR4, a novel epidermal growth factor (EGF)-TM7 molecule up-regulated in activated mouse macrophages, binds to a putative cellular ligand on B lymphoma cell line A20. J Biol Chem 2002; 277(32):29283–29293.PubMedCrossRefGoogle Scholar
  31. 31.
    O’Reilly D, Addley M, Quinn C et al. Functional analysis of the murine Emrl promoter identifies a novel purine-rich regulatory motif required for high-level gene expression in macrophages. Genomics 2004; 84(6):1030–1040.PubMedCrossRefGoogle Scholar
  32. 32.
    Moriguchi T, Hamada M, Morito N et al. MafB is essential for renal development and F4/80 expression in macrophages. Mol Cell Biol 2006; 26(15):5715–5727.PubMedCrossRefGoogle Scholar
  33. 33.
    Nakamura M, Hamada M, Hasegawa K et al. c-Maf is essential for the F4/80 expression in macrophages in vivo. Gene 2009; 445(1-2):66–72.PubMedCrossRefGoogle Scholar
  34. 34.
    Warschkau H, Kiderlen AF. A monoclonal antibody directed against the murine macrophage surface molecule F4/80 modulates natural immune response to Listeria monocytogenes. J Immunol 1999; 163(6):3409–3416.PubMedGoogle Scholar
  35. 35.
    Stein-Streilein J. Immune regulation and the eye. Trends Immunol 2008; 29(11):548–554.PubMedCrossRefGoogle Scholar
  36. 36.
    Stein-Streilein J, Taylor AW. An eye’s view of T regulatory cells. J Leukoc Biol 2007; 81(3):593–598.PubMedCrossRefGoogle Scholar
  37. 37.
    Niederkorn JY. See no evil, hear no evil, do no evil: the lessons of immune privilege. Nat Immunol 2006; 7(4):354–359.PubMedCrossRefGoogle Scholar
  38. 38.
    Faunce DE, Stein-Streilein J. NKT cell-derived RANTES recruits APCs and CD8+ T-cells to the spleen during the generation of regulatory T-cells in tolerance. J Immunol 2002; 169(1):31–38.PubMedGoogle Scholar
  39. 39.
    Hara Y, Caspi RR, Wiggert B et al. Analysis of an in vitro-generated signal that induces systemic immune deviation similar to that elicited by antigen injected into the anterior chamber of the eye. J Immunol 1992; 149(5):1531–1538.PubMedGoogle Scholar
  40. 40.
    Wilbanks GA, Mammolenti M, Streilein JW. Studies on the induction of anterior chamber-associated immune deviation (ACAID). II. Eye-derived cells participate in generating blood-borne signals that induce ACAID. J Immunol 1991; 146(9):3018–3024.PubMedGoogle Scholar
  41. 41.
    Wilbanks GA, Streilein JW. Studies on the induction of anterior chamber-associated immune deviation (ACAID). 1. Evidence that an antigen-specific, ACAID-inducing, cell-associated signal exists in the peripheral blood. J Immunol 1991; 146(8):2610–2617.PubMedGoogle Scholar
  42. 42.
    Lin HH, Chang GW, Huang YS et al. Multivalent protein probes for the identification and characterization of cognate cellular ligands for myeloid cell surface receptors. Methods Mol Biol 2009; 531:89–101.PubMedCrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Hsi-Hsien Lin
    • 1
  • Martin Stacey
  • Joan Stein-Streilein
  • Siamon Gordon
  1. 1.Department of Microbiology and Immunology, College of MedicineChang Gung UniversityKwei-SanTaiwan

Personalised recommendations