Regulation of myeloid cell proliferation and survival by p75/AIRM1 and CD33 surface receptors

  • Maria Cristina Mingari
  • Chiara Vitale
  • Chiara Romagnani
  • Michela Falco
  • Lorenzo Moretta
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 495)


Major progresses have recently been made toward a better understanding of the molecular mechanisms regulating the NK cell function. This is primarily the result of the discovery of a number of receptors which regulate the NK cell function. Thus, the identification of various MHC-class I-specific inhibitory NK receptors (iNKR) revealed a sophisticated capability of discriminating between normal and tumor (or virally-infected) cells (1-4). All iNKR are characterized by the presence of an immunoreceptor tyrosine-based inhibition motif (ITIM) in their cytoplasmic tail (3-6). The surface expression of iNKR that inhibit the NK-cell function, explains why NK cells lyse only those target cells that have lost or express insufficient amounts of MHC class I molecules, a phenomenon that frequently occurs in tumors and virus-infected cells. Each inhibitory receptor is expressed only by a fraction of NK cells. In addition, each NK cell expresses at least one receptor specific for self-MHC alleles. As a consequence, the whole NK cell pool can sense the loss of even single MHC-class I alleles on self cells. NK cells also express surface receptors responsible for the activation during the process of natural cytotoxicity. These recently identified receptors include NKp46 (7 8), NKp30 (9) and NKp44 (10 11), collectively referred to as natural cytotoxicity receptors (NCR) (12). Another receptor which plays a complementary role with NCR in the processo of NK cell activation is NKG2D (13 14), while additional triggering surface molecules expressed by human NK cells, including 2B4 and NKp80, appear to play a role as coreceptors rather than as true receptors (15 16).


Acute Myeloid Leukemia Inhibitory Receptor Acute Myeloid Leukemia Cell Tumor Cell Lysis Human Natural Killer Cell 
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.
    Trinchieri G. Biology of natural killer cells. Adv. Immunol. 1989; 47: 176–187Google Scholar
  2. 2.
    Ljunggren HG and Karre K. In search of the “missing self”. MHC molecules and NK cell recognition. Immunol. Today 1990; 11:237–244Google Scholar
  3. 3.
    Moretta A, Bottino C, Vitale M, Pende D, Biassoni R, Mingari MC and Moretta L.. Receptors for HLA-class I molecules in human Natural Killer cells. Annu. Rev. Immunol. 1996; 14: 619–648PubMedCrossRefGoogle Scholar
  4. 4.
    Lanier LL. NK cell receptors. Annu. Rev. Immunol. 1998; 16:359–393PubMedCrossRefGoogle Scholar
  5. 5.
    Long EO. Regulation of immune responses through inhibitory receptors. Annu. Rev. Immunol. 1999; 17: 875–804PubMedCrossRefGoogle Scholar
  6. 6.
    Bolland S, Ravetch JV. Inhibitory pathways triggered by ITIM containing receptors. Adv Immunol. 1999; 72: 149–177PubMedCrossRefGoogle Scholar
  7. 7.
    Sivori S et al. NKp46, a novel Natural Killer cell-specific surface molecule which mediates cell activation. J.Exp. Med. 1997; 186: 1129–1136PubMedCrossRefGoogle Scholar
  8. 8.
    Pessino A et al. Molecular cloning of NKp46: a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity. J. Exp. Med. 1998. 188: 953–960PubMedCrossRefGoogle Scholar
  9. 9.
    Pende D et al. Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J. Exp. Med. 1999; 190: 1505–1516PubMedCrossRefGoogle Scholar
  10. 10.
    Vitale M et al. NKp44, a novel triggering surface molecule specifically expressed by activated Natural Killer cells is involved in non-MHC restricted tumor cell lysis. J. Exp. Med. 1998; 187: 2065–2072.PubMedCrossRefGoogle Scholar
  11. 11.
    Cantoni C et al. NKp44, a triggering receptor involved in tumor cell lysis by activated human Natural Killer cells, is a novel member of the immunoglobulin superfamily. J. Exp. Med. 1999; 189:787–796PubMedCrossRefGoogle Scholar
  12. 12.
    Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999; 285:727–729.PubMedCrossRefGoogle Scholar
  13. 13.
    Pende D et al. Role of NKG2D in tumor cell lysis mediated by human NK cells: cooperation with natural cytotoxicity receptors and capability of recognizing tumors of nonepithelial origin. Eur. J. Immunol. 2001; 31 (in press)Google Scholar
  14. 14.
    Sivori S et al. 2B4 functions as a co-receptor in human natural killer cell activation. Eur. J. Immunol. 2000; 30: 787–793PubMedCrossRefGoogle Scholar
  15. 15.
    Moretta A, Biassoni R, Bottino C, Mingari MC, and Moretta L.. Natural Cytotoxicity Receptors that trigger human NK-mediated cytolysis. Immunol. Today 2000; 21:228–234.Google Scholar
  16. 16.
    Vitale M et al. Identification of NKp80 a novel triggering molecule expressed by human Natural Killer cells. Eur. J. Immunol. 2001; 31: 233–242PubMedCrossRefGoogle Scholar
  17. 17.
    Mingari, MC, Vitale C, Cambiaggi A, Schiavetti F, Melioli G, Ferrini S, Poggi, A. Cytolytic T lymphocytes displaying Natural Killer (NK)-like activity. Expression of NKrelated functional receptors for HLA class I molecules (p58 and CD94) and inhibitory effect on the TCR-mediated target cell lysis or lymphokine production. Int Immunol. 1995; 7:697–703PubMedCrossRefGoogle Scholar
  18. 18.
    Mingari MC et al. Human CD8+ T lymphocyte subsets that express HLA class I-specific inhibitory receptors represent oligoclonally or monoclonally expanded cell populations. Proc. Natl. Acad. Sci. USA. 1996; 93:12433–12438PubMedCrossRefGoogle Scholar
  19. 19.
    Mingari MC, Moretta A, Moretta L. Regulation of KIR expression in human T lymphocytes. A safety mechanism which may impair protective T cell responses. Immunol. Today 1998; 19:153–157Google Scholar
  20. 20.
    Falco M et al. Identification and molecular cloning of p75/AIRM1, a novel member of the sialoadhesin family which functions as an inhibitory receptor in human natural killer cells. J. Exp. Med. 1999; 190:793–802PubMedCrossRefGoogle Scholar
  21. 21.
    Poggi A et al. p40, a novel surface molecule involved in the regulation of the non-MHC restricted cytolytic activity in humans. Eur. J. Immunol. 1995; 25:369–376PubMedCrossRefGoogle Scholar
  22. 22.
    Meyaard L, Adema GJ, Chang C, Woollatt E, Sutherland GR, Lanier LL, Phillips JH. LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes. Immunity 1997; 7:283–290PubMedCrossRefGoogle Scholar
  23. 23.
    Cantoni C et al. Molecular and functional characterization of IRp60, a member of the immunoglobulin superfamily that functions as an inhibitory receptor in human natural killer cells. Eur. J. Immunol. 1999; 29:3148–3159PubMedCrossRefGoogle Scholar
  24. 24.
    Peiper SC, Ashmun RA, Look AT. Molecular cloning, expression, and chromosomal localization of a human gene encodong the CD33 myeloid differentiation antigen. Blood 1988; 72:314–321PubMedGoogle Scholar
  25. 25.
    Freeman SD, Kelm S, Barber KE, and Crocker PR. Characterization of CD33 as a new member of the sialoadhesin family of cellular interaction molecules. Blood 1995; 85: 2005–2012.PubMedGoogle Scholar
  26. 26.
    Caron PC et al. Murine and humanized constructs of monoclonal antibody M195 (antiCD33) for the therapy of acute myelogenous leukemia. Cancer 1994; 73: 1049–1056PubMedCrossRefGoogle Scholar
  27. 27.
    Taylor VC, Buckley CD, Douglas M, Cody AJ, Simmons DL, and Freeman SD. The myeloid-specific sialic acid binding receptor, CD33, associates with the protein-tyrosine phosphatases,SHP-1 and SHP-2. J.Biol.Chem. 1999; 274: 11505–11512.PubMedCrossRefGoogle Scholar
  28. 28.
    Ulyanova T, Blasioli J, Woodford-Thomas TA, and Thomas ML. The sialoadhesin CD33 is a myeloid-specific inhibitory receptor. Eur. J. Immunol. 1999; 29: 3440–3449.PubMedCrossRefGoogle Scholar
  29. 29.
    Sujatha PP, Taylor LS, Stransbury EK, and McVicar DV. Myeloid specific human CD33 is an inhibitory receptor with differential ITIM function in recruiting the phosphatases SHP-1 and SHP-2. Blood 2000; 96, 483–490.Google Scholar
  30. 30.
    Vitale C et al. Engagement of p75/AIRM1 or CD33 inhibits the proliferation of normal or leukemic myeloid cells. Proc. Natl. Acad. Sci. USA 1999; 96: 15091–15096.PubMedCrossRefGoogle Scholar
  31. 31.
    Vitale C et al. Surface Expression and function of p75/AIRM-1 or CD33 in acute myeloid leukemias. Engagement of CD33 induces apoptosis of leukemic cells. Proc.Natl.Acad.Sci. USA. 2001; in press.Google Scholar
  32. 32.
    Ferlazzo, G, Spaggiari GM, Semino C, Melioli G, and Moretta L. Engagement of CD33 surface molecules prevents the generation of dendritic cells from both monocytes and CD34+ myeloid precursors. Eur. J. Immunol. 2000; 30: 827–833.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Maria Cristina Mingari
    • 1
    • 2
  • Chiara Vitale
    • 3
  • Chiara Romagnani
    • 2
  • Michela Falco
    • 3
    • 4
  • Lorenzo Moretta
    • 3
    • 4
  1. 1.Istituto Nazionale per la Ricerca sul Cancro c/o Centro Biotecnologie AvanzateGenova
  2. 2.Dipartimento di Oncologia, Biologia e GeneticaUniversità degli Studi di GenovaGenovaItaly
  3. 3.Dipartimento di Medicina SperimentaleUniversità degli Studi di GenovaGenovaItaly
  4. 4.lstituto Giannina GasliniGenovaItaly

Personalised recommendations