Skip to main content
SpringerLink
Log in

The CD2 Family of Natural Killer Cell Receptors

  • Chapter
Immunobiology of Natural Killer Cell Receptors

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 298))

Abstract

The CD2 family of receptors is evolutionarily conserved and widely expressed on cells within the hematopoietic compartment. In recent years several new members have been identified with important roles in the immune system. CD2 family members regulate natural killer (NK) cell lytic activity and inflammatory cytokine production when engaged by ligands on tumor cells. Furthermore, a subfamily of CD2 receptors, the CD150-like molecules, has been implicated in the pathogenesis of X-linked lymphoproliferative disease (XLP). Many of these receptors have now been shown to bind homophilically or heterophilically to other molecules within the family. With these discoveries a novel mechanism for lymphocyte regulation has emerged: CD2 family members on NK cells engage ligands on neighboring NK cells, leading to NK cell stimulation. Moreover, heterotypic stimulatory interactions between NK cells and other leukocytes also occur. In this manner, CD2 family members may provide interlymphocyte communication that maintains organization within the hematopoietic compartment and amplifies immune responses. This review discusses these multiple roles for CD2 family members, focusing specifically on the regulation of NK cells.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Aoukaty A, Tan R (2002) Association of the X-linked lymphoproliferative disease gene product SAP/SH2D1A with 2B4, a natural killer cell-activating molecule, is dependent on phosphoinositide 3-kinase. J Biol Chem 277: 13331–13337

    Article  CAS  PubMed  Google Scholar 

  • Assarsson E, Kambayashi T, Schatzle JD, Cramer SO, von Bonin A, Jensen PE, Ljunggren HG, Chambers BJ (2004) NK cells stimulate proliferation of T and NK cells through 2B4/CD48 interactions. J Immunol 173:174–180

    CAS  PubMed  Google Scholar 

  • Barber DF, Long EO (2003) Coexpression of CD58 or CD48 with intercellular adhesion molecule 1 on target cells enhances adhesion of resting NK cells. J Immunol 170:294–299

    CAS  PubMed  Google Scholar 

  • Bell GM, Bolen JB, Imboden JB (1992) Association of Src-like protein tyrosine kinases with the CD2 cell surface molecule in rat T lymphocytes and natural killer cells. Mol Cell Biol 12:5548–5554

    CAS  PubMed  Google Scholar 

  • Bell GM, Fargnoli J, Bolen JB, Kish L, Imboden JB (1996) The SH3 domain of p56lck binds to proline-rich sequences in the cytoplasmic domain of CD2. J Exp Med 183:169–178

    Article  CAS  PubMed  Google Scholar 

  • Benoit L, Wang X, Pabst HF, Dutz J, Tan R (2000) Defective NK cell activation in X-linked lymphoproliferative disease. J Immunol 165:3549–3553

    CAS  PubMed  Google Scholar 

  • Bierer BE, Sleckman BP, Ratnofsky SE, Burakoff SJ (1989) The biologic roles of CD2, CD4, and CD8 in T-cell activation. Annu Rev Immunol 7:579–599

    Article  CAS  PubMed  Google Scholar 

  • Boles KS, Mathew PA (2001) Molecular cloning of CS1, a novel human natural killer cell receptor belonging to the CD2 subset of the immunoglobulin superfamily. Immunogenetics 52:302–307

    Article  CAS  PubMed  Google Scholar 

  • Boles KS, Nakajima H, Colonna M, Chuang SS, Stepp SE, Bennett M, Kumar V, Mathew PA (1999) Molecular characterization of a novel human natural killer cell receptor homologous to mouse 2B4. Tissue Antigens 54: 27–34

    Article  CAS  PubMed  Google Scholar 

  • Boles KS, Stepp SE, Bennett M, Kumar V, Mathew PA (2001) 2B4 (CD244) and CS1: novel members of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes. Immunol Rev 181: 234–249

    Article  CAS  PubMed  Google Scholar 

  • Bolhuis RL, Roozemond RC, van de Griend RJ (1986) Induction and blocking of cytolysis in CD2+, CD3-NK and CD2+, CD3+ cytotoxic T lymphocytes via CD2 50 KD sheep erythrocyte receptor. J Immunol 136:3939–3944

    CAS  PubMed  Google Scholar 

  • Borca MV, Carrillo C, Zsak L, Laegreid WW, Kutish GF, Neilan JG, Burrage TG, Rock DL (1998) Deletion of a CD2-like gene, 8-DR, from African swine fever virus affects viral infection in domestic swine. J Virol 72: 2881–2889

    CAS  PubMed  Google Scholar 

  • Bottino C, Augugliaro R, Castriconi R, Nanni M, Biassoni R, Moretta L, Moretta A (2000) Analysis of the molecular mechanism involved in 2B4-mediated NK cell activation: evidence that human 2B4 is physically and functionally associated with the linker for activation of T cells. Eur J Immunol 30:3718–3722

    Article  CAS  PubMed  Google Scholar 

  • Bottino C, Falco M, Parolini S, Marcenaro E, Augugliaro R, Sivori S, Landi E, Biassoni R, Notarangelo LD, Moretta L, Moretta A (2001) NTB-A, a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked lymphoproliferative disease. J Exp Med 194: 235–246

    Article  CAS  PubMed  Google Scholar 

  • Bouchon A, Cella M, Grierson HL, Cohen JI, Colonna M (2001) Activation of NK cell-mediated cytotoxicity by a SAP-independent receptor of the CD2 family. J Immunol 167:5517–5521

    CAS  PubMed  Google Scholar 

  • Brown MH, Boles K, van der Merwe PA, Kumar V, Mathew PA, Barclay AN (1998) 2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48. J Exp Med 188:2083–2090

    Article  CAS  PubMed  Google Scholar 

  • Chan B, Lanyi A, Song HK, Griesbach J, Simarro-Grande M, Poy F, Howie D, Sumegi J, Terhorst C, Eck MJ (2003) SAP couples Fyn to SLAM immune receptors. Nat Cell Biol 5:155–160

    Article  CAS  PubMed  Google Scholar 

  • Chavin KD, Qin L, Lin J, Woodward J, Baliga P, Kato K, Yagita H, Bromberg JS (1994) Anti-CD48 (murine CD2 ligand) mAbs suppress cell mediated immunity in vivo. Int Immunol 6:701–709

    CAS  PubMed  Google Scholar 

  • Chen R, Relouzat F, Roncagalli R, Aoukaty A, Tan R, Latour S, Veillette A (2004) Molecular dissection of 2B4 signaling: implications for signal transduction by SLAM-related receptors. Mol Cell Biol 24:5144–5156

    Article  CAS  PubMed  Google Scholar 

  • Chuang SS, Kumaresan PR, Mathew PA (2001) 2B4 (CD244)-mediated activation of cytotoxicity and IFN-γ release in human NK cells involves distinct pathways. J Immunol 167:6210–6216

    CAS  PubMed  Google Scholar 

  • Chung B, Aoukaty A, Dutz J, Terhorst C, Tan R (2005) Signaling lymphocytic activation molecule-associated protein controls NKT cell functions. J Immunol 174:3153–3157

    CAS  PubMed  Google Scholar 

  • Cocks BG, Chang CC, Carballido JM, Yssel H, de Vries JE, Aversa G (1995) A novel receptor involved in T-cell activation. Nature 376:260–263

    Article  CAS  PubMed  Google Scholar 

  • Coffey AJ, Brooksbank RA, Brandau O, Oohashi T, Howell GR, Bye JM, Cahn AP, Durham J, Heath P, Wray P, Pavitt R, Wilkinson J, Leversha M, Huckle E, Shaw-Smith CJ, Dunham A, Rhodes S, Schuster V, Porta G, Yin L, Serafini P, Sylla B, Zollo M, Franco B, Bentley DR, et al. (1998) Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet 20:129–135

    Article  CAS  PubMed  Google Scholar 

  • Collins TL, Kassner PD, Bierer BE, Burakoff SJ (1994) Adhesion receptors in lymphocyte activation. Curr Opin Immunol 6:385–393

    Article  CAS  PubMed  Google Scholar 

  • Crawford K, Gabuzda D, Pantazopoulos V, Xu J, Clement C, Reinherz E, Alper CA (1999) Circulating CD2+ monocytes are dendritic cells. J Immunol 163:5920–5928

    CAS  PubMed  Google Scholar 

  • Crawford K, Stark A, Kitchens B, Sternheim K, Pantazopoulos V, Triantafellow E, Wang Z, Vasir B, Larsen CE, Gabuzda D, Reinherz E, Alper CA (2003) CD2 engagement induces dendritic cell activation: implications for immune surveillance and T-cell activation. Blood 102:1745–1752

    Article  CAS  PubMed  Google Scholar 

  • Czar MJ, Kersh EN, Mijares LA, Lanier G, Lewis J, Yap G, Chen A, Sher A, Duckett CS, Ahmed R, Schwartzberg PL (2001) Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP. Proc Natl Acad Sci USA 98:7449–7454

    Article  CAS  PubMed  Google Scholar 

  • Davis SJ, Ikemizu S, Wild MK, van der Merwe PA (1998) CD2 and the nature of protein interactions mediating cell-cell recognition. Immunol Rev 163:217–236

    Article  CAS  PubMed  Google Scholar 

  • de la Fuente MA, Pizcueta P, Nadal M, Bosch J, Engel P (1997) CD84 leukocyte antigen is a new member of the Ig superfamily. Blood 90:2398–2405

    PubMed  Google Scholar 

  • de la Fuente MA, Tovar V, Villamor N, Zapater N, Pizcueta P, Campo E, Bosch J, Engel P (2001) Molecular characterization and expression of a novel human leukocyte cell-surface marker homologous to mouse Ly-9. Blood 97: 3513–3520

    Article  PubMed  Google Scholar 

  • Degli-Esposti MA, Smyth MJ (2005) Close encounters of different kinds: dendritic cells and NK cells take centre stage. Nat Rev Immunol 5:112–124

    Article  CAS  PubMed  Google Scholar 

  • Dikic I (2002) CIN85/CMS family of adaptor molecules. FEBS Lett 529:110–115

    Article  CAS  PubMed  Google Scholar 

  • Durda PJ, Boos SC, Gottlieb PD (1979) T100: a new murine cell surface glycoprotein detected by anti-Lyt-2.1 serum. J Immunol 122:1407–1412

    CAS  PubMed  Google Scholar 

  • Dustin ML, Olszowy MW, Holdorf AD, Li J, Bromley S, Desai N, Widder P, Rosenberger F, van der Merwe PA, Allen PM, Shaw AS (1998) A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts. Cell 94:667–677

    Article  CAS  PubMed  Google Scholar 

  • Dustin ML, Selvaraj P, Mattaliano RJ, Springer TA (1987) Anchoring mechanisms for LFA-3 cell adhesion glycoprotein at membrane surface. Nature 329:846–848

    Article  CAS  PubMed  Google Scholar 

  • Dykstra M, Cherukuri A, Sohn HW, Tzeng SJ, Pierce SK (2003) Location is everything: lipid rafts and immune cell signaling. Annu Rev Immunol 21:457–481

    Article  CAS  PubMed  Google Scholar 

  • Eissmann P, Beauchamp L, Wooters J, Tilton JC, Long EO, Watzl C (2005) Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244). Blood 105:4722–4729

    Article  CAS  PubMed  Google Scholar 

  • Falco M, Marcenaro E, Romeo E, Bellora F, Marras D, Vely F, Ferracci G, Moretta L, Moretta A, Bottino C (2004) Homophilic interaction of NTBA, a member of the CD2 molecular family: induction of cytotoxicity and cytokine release in human NK cells. Eur J Immunol 34:1663–1672

    Article  CAS  PubMed  Google Scholar 

  • Fennelly JA, Tiwari B, Davis SJ, Evans EJ (2001) CD2F-10: a new member of the CD2 subset of the immunoglobulin superfamily. Immunogenetics 53:599–602

    Article  CAS  PubMed  Google Scholar 

  • Flaig RM, Stark S, Watzl C (2004) Cutting edge:NTB-Aactivates NK cells viahomophilic interaction. J Immunol 172:6524–6527

    CAS  PubMed  Google Scholar 

  • Fletcher JM, Prentice HG, Grundy JE (1998) Natural killer cell lysis of cytomegalovirus (CMV)-infected cells correlates with virally induced changes in cell surface Lymphocyte Function-Associated Antigen-3 (LFA-3) expression and not with the CMV-induced down-regulation of cell surface class I HLA. J Immunol 161:2365–2374

    CAS  PubMed  Google Scholar 

  • Fraser CC, Howie D, Morra M, Qiu Y, Murphy C, Shen Q, Gutierrez-Ramos JC, Coyle A, Kingsbury GA, Terhorst C (2002) Identification and characterization of SF2000 and SF2001, two new members of the immune receptor SLAM/CD2 family. Immunogenetics 53:843–850

    Article  CAS  PubMed  Google Scholar 

  • Garnett D, Barclay AN, Carmo AM, Beyers AD (1993) The association of the protein tyrosine kinases p56lck and p60fyn with the glycosyl phosphatidylinositolanchored proteins Thy-1 and CD48 in rat thymocytes is dependent on the state of cellular activation. Eur J Immunol 23:2540–2544

    CAS  PubMed  Google Scholar 

  • Garni-Wagner BA, Purohit A, Mathew PA, Bennett M, Kumar V (1993) A novel function-associated molecule related to non-MHC-restricted cytotoxicity mediated by activated natural killer cells and T cells. J Immunol 151:60–70

    CAS  PubMed  Google Scholar 

  • Gonzalez-Cabrero J, Wise CJ, Latchman Y, Freeman GJ, Sharpe AH, Reiser H (1999) CD48-deficient mice have a pronounced defect in CD4+ T cell activation. Proc Natl Acad Sci USA 96:1019–1023

    Article  CAS  PubMed  Google Scholar 

  • Hogarth PM, Craig J, McKenzie IF (1980) Amonoclonal antibody detecting the Ly-9.2 (Lgp 100) cell-membrane alloantigen. Immunogenetics 11:65–74

    Article  CAS  PubMed  Google Scholar 

  • Howie D, Laroux FS, Morra M, Satoskar AR, Rosas LE, Faubion WA, Julien A, Rietdijk S, Coyle AJ, Fraser C, Terhorst C (2005) Cutting Edge: The SLAM family receptor Ly108 controls T cell and neutrophil functions. J Immunol 174:5931–5935

    CAS  PubMed  Google Scholar 

  • Kambayashi T, Assarsson E, Chambers BJ, Ljunggren HG (2001) Cutting edge: Regulation of CD8+ T cell proliferation by 2B4/CD48 interactions. J Immunol 167:6706–6710

    CAS  PubMed  Google Scholar 

  • Killeen N, Moessner R, Arvieux J, Willis A, Williams AF (1988) The MRC OX-45 antigen of rat leukocytes and endothelium is in a subset of the immunoglobulin superfamily with CD2, LFA-3 and carcinoembryonic antigens. EMBO J 7:3087–3091

    CAS  PubMed  Google Scholar 

  • Killeen N, Stuart SG, Littman DR (1992) Development and function of T cells in mice with a disrupted CD2 gene. EMBO J 11:4329–4336

    CAS  PubMed  Google Scholar 

  • King PD, Sadra A, Han A, Liu XR, Sunder-Plassmann R, Reinherz EL, Dupont B (1996) CD2 signaling in T cells involves tyrosine phosphorylation and activation of the Tec family kinase, EMT/ITK/TSK. Int Immunol 8: 1707–1714

    CAS  PubMed  Google Scholar 

  • Kingma DW, Imus P, Xie XY, Jasper G, Sorbara L, Stewart C, Stetler-Stevenson M (2002) CD2 is expressed by a subpopulation of normal B cells and is frequently present in mature B-cell neoplasms. Cytometry 50:243–248

    Article  PubMed  Google Scholar 

  • Kingsbury GA, Feeney LA, Nong Y, Calandra SA, Murphy CJ, Corcoran JM, Wang Y, Prabhu Das MR, Busfield SJ, Fraser CC, Villeval JL (2001) Cloning, expression, and function of BLAME, a novel member of the CD2 family. J Immunol 166:5675–5680

    CAS  PubMed  Google Scholar 

  • Klem J, Verrett PC, Kumar V, Schatzle JD (2002) 2B4 is constitutively associated with linker for the activation of T cells in glycolipid-enriched microdomains:properties required for 2B4 lytic function. J Immunol 169:55–62

    CAS  PubMed  Google Scholar 

  • Kozak CA, Davidson WF, Morse HC, 3rd (1984) Genetic and functional relationships of the retroviral and lymphocyte alloantigen loci on mouse chromosome 1. Immunogenetics 19:163–168

    Article  CAS  PubMed  Google Scholar 

  • Krause SW, Rehli M, Heinz S, Ebner R, Andreesen R (2000) Characterization of MAX.3 antigen, a glycoprotein expressed on mature macrophages, dendritic cells and blood platelets: identity with CD84. Biochem J 346: 729–736

    Article  CAS  PubMed  Google Scholar 

  • Kruse M, Meinl E, Henning G, Kuhnt C, Berchtold S, Berger T, Schuler G, Steinkasserer A (2001) Signaling lymphocytic activation molecule is expressed on mature CD83+ dendritic cells and is up-regulated by IL-1β. J Immunol 167:1989–1995

    CAS  PubMed  Google Scholar 

  • Kubin MZ, Parshley DL, Din W, Waugh JY, Davis-Smith T, Smith CA, Macduff BM, Armitage RJ, Chin W, Cassiano L, Borges L, Petersen M, Trinchieri G, Goodwin RG (1999) Molecular cloning and biological characterization of NK cell activation-inducing ligand, a counterstructure for CD48. Eur J Immunol 29:3466–3477

    Article  CAS  PubMed  Google Scholar 

  • Kubota K (2002) A structurally variant formof the 2B4 antigen is expressed on the cell surface of mouse mast cells. Microbiol Immunol 46:589–592

    CAS  PubMed  Google Scholar 

  • Kumar V, McNerney ME (2005) A new self: MHC-class-I-independent natural-killer-cell self-tolerance. Nat Rev Immunol 5:363–374

    Article  CAS  PubMed  Google Scholar 

  • Kumaresan PR, Lai WC, Chuang SS, Bennett M, Mathew PA (2002) CS1, a novel member of the CD2 family, is homophilic and regulates NK cell function. Mol Immunol 39:1–8

    Article  CAS  PubMed  Google Scholar 

  • Lanier LL (1998) NK cell receptors. Annu Rev Immunol 16:359–393

    Article  CAS  PubMed  Google Scholar 

  • Lanier LL (2005) NK cell recognition. Annu Rev Immunol 23:225–274.

    Article  CAS  PubMed  Google Scholar 

  • Lanier LL, Corliss B, Phillips JH (1997) Arousal and inhibition of human NK cells. Immunol Rev 155: 145–154

    Article  CAS  PubMed  Google Scholar 

  • Latchman Y, McKay PF, Reiser H (1998) Identification of the 2B4 molecule as a counterreceptor for CD48. J Immunol 161:5809–5812

    CAS  PubMed  Google Scholar 

  • Latour S, Gish G, Helgason CD, Humphries RK, Pawson T, Veillette A (2001) Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene product. Nat Immunol 2:681–690

    Article  CAS  PubMed  Google Scholar 

  • Latour S, Roncagalli R, Chen R, Bakinowski M, Shi X, Schwartzberg PL, Davidson D, Veillette A (2003) Binding of SAP SH2 domain to FynT SH3 domain reveals a novel mechanism of receptor signalling in immune regulation. Nat Cell Biol 5:149–154

    Article  CAS  PubMed  Google Scholar 

  • Lee JK, Boles KS, Mathew PA (2004a) Molecular and functional characterization of a CS1 (CRACC) splice variant expressed in human NK cells that does not contain immunoreceptor tyrosine-based switch motifs. Eur J Immunol 34: 2791–2799

    Article  CAS  PubMed  Google Scholar 

  • Lee KM, Bhawan S, Majima T, Wei H, Nishimura MI, Yagita H, Kumar V (2003) Cutting edge: the NK cell receptor 2B4 augments antigen-specific T cell cytotoxicity through CD48 ligation on neighboring T cells. J Immunol 170: 4881–4885

    CAS  PubMed  Google Scholar 

  • Lee KM, Forman JP, McNerney ME, Stepp SE, Kuppireddi S, Guzior D, Latchman YE, Sayegh MH, Yagita H, Oh SB, Wulfing C, Schatzle J, Mathew PA, Sharpe AH, Kumar V (2005) Requirement of homotypic NK cell interactions through 2B4(CD244)/CD48 in the generation of NK effector functions. Blood:DOI 10.1182/blood-2005-1101-0185

    Google Scholar 

  • Lee KM, McNerney ME, Stepp SE, Mathew PA, Schatzle JD, Bennett M, Kumar V (2004b) 2B4 acts as a non-major histocompatibility complex binding inhibitory receptor on mouse natural killer cells. J Exp Med 199: 1245–1254

    Article  CAS  PubMed  Google Scholar 

  • Li C, Iosef C, Jia CY, Han VK, Li SS (2003) Dual functional roles for the X-linked lymphoproliferative syndrome gene product SAP/SH2D1A in signaling through the signaling lymphocyte activation molecule (SLAM) family of immune receptors. J Biol Chem 278:3852–3859

    Article  CAS  PubMed  Google Scholar 

  • Lodoen MB, Lanier LL (2005) Viral modulation of NK cell immunity. Nat Rev Microbiol 3:59–69

    Article  CAS  PubMed  Google Scholar 

  • Martelli MP, Lin H, Zhang W, Samelson LE, Bierer BE (2000) Signaling via LAT (linker for T-cell activation) and Syk/ZAP70 is required for ERK activation and NFAT transcriptional activation following CD2 stimulation. Blood 96: 2181–2190

    CAS  PubMed  Google Scholar 

  • Martin M, Del Valle JM, Saborit I, Engel P (2005) Identification of Grb2 as a novel binding partner of the signaling lymphocytic activation molecule-associated protein binding receptor CD229. J Immunol 174:5977–5986

    CAS  PubMed  Google Scholar 

  • Martin M, Romero X, de la Fuente MA, Tovar V, Zapater N, Esplugues E, Pizcueta P, Bosch J, Engel P (2001) CD84 functions as a homophilic adhesion molecule and enhances IFN-. secretion: adhesion is mediated by Ig-like domain 1. J Immunol 167:3668–3676

    CAS  PubMed  Google Scholar 

  • Mathieson BJ, Sharrow SO, Bottomly K, Fowlkes BJ (1980) Ly 9, an alloantigenic marker of lymphocyte differentiation. J Immunol 125:2127–2136

    CAS  PubMed  Google Scholar 

  • Mavaddat N, Mason DW, Atkinson PD, Evans EJ, Gilbert RJ, Stuart DI, Fennelly JA, Barclay AN, Davis SJ, Brown MH (2000) Signaling lymphocytic activation molecule (CDw150) is homophilic but self-associates with very low affinity. J Biol Chem 275:28100–28109

    CAS  PubMed  Google Scholar 

  • McNerney ME, Guzior D, Kumar V (2005) 2B4 (CD244)-CD48 interactions provide a novel MHC class I-independent system for NK cell self-tolerance in mice. Blood:DOI 10.1182/blood-2005-1101-0357

    Google Scholar 

  • Moingeon P, Lucich JL, McConkey DJ, Letourneur F, Malissen B, Kochan J, Chang HC, Rodewald HR, Reinherz EL (1992) CD3ζ dependence of the CD2 pathway of activation in T lymphocytes and natural killer cells. Proc Natl Acad Sci USA 89:1492–1496

    CAS  PubMed  Google Scholar 

  • Mooney JM, Klem J, Wulfing C, Mijares LA, Schwartzberg PL, Bennett M, Schatzle JD (2004) The murine NK receptor 2B4 (CD244) exhibits inhibitory function independent of signaling lymphocytic activation molecule-associated protein expression. J Immunol 173:3953–3961

    CAS  PubMed  Google Scholar 

  • Moran M, Miceli MC (1998) Engagement of GPI-linked CD48 contributes to TCR signals and cytoskeletal reorganization: a role for lipid rafts in T cell activation. Immunity 9:787–796

    Article  CAS  PubMed  Google Scholar 

  • Morra M, Lu J, Poy F, Martin M, Sayos J, Calpe S, Gullo C, Howie D, Rietdijk S, Thompson A, Coyle AJ, Denny C, Yaffe MB, Engel P, Eck MJ, Terhorst C (2001) Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells. EMBO J 20:5840–5852

    Article  CAS  PubMed  Google Scholar 

  • Munitz A, Bachelet I, Fraenkel S, Katz G, Mandelboim O, Simon HU, Moretta L, Colonna M, Levi-Schaffer F (2005) 2B4 (CD244) is expressed and functional on human eosinophils. J Immunol 174:110–118

    CAS  PubMed  Google Scholar 

  • Musgrave BL, Watson CL, Haeryfar SM, Barnes CA, Hoskin DW (2004) CD2-CD48 interactions promote interleukin-2 and interferon-γ synthesis by stabilizing cytokine mRNA. Cell Immunol 229:1–12

    Article  CAS  PubMed  Google Scholar 

  • Musgrave BL, Watson CL, Hoskin DW (2003) CD2-CD48 interactions promote cytotoxic T lymphocyte induction and function: anti-CD2 and anti-CD48 antibodies impair cytokine synthesis, proliferation, target recognition/adhesion, and cytotoxicity. J Interferon Cytokine Res 23:67–81

    Article  CAS  PubMed  Google Scholar 

  • Nakajima H, Cella M, Bouchon A, Grierson HL, Lewis J, Duckett CS, Cohen JI, Colonna M (2000) Patients with X-linked lymphoproliferative disease have a defect in 2B4 receptor-mediated NK cell cytotoxicity. Eur J Immunol 30:3309–3318

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Takahashi K, Fukazawa T, Koyanagi M, Yokoyama A, Kato H, Yagita H, Okumura K (1990) Relative contribution of CD2 and LFA-1 to murine T and natural killer cell functions. J Immunol 145:3628–3634

    CAS  PubMed  Google Scholar 

  • Nichols KE, Harkin DP, Levitz S, Krainer M, Kolquist KA, Genovese C, Bernard A, Ferguson M, Zuo L, Snyder E, Buckler AJ, Wise C, Ashley J, Lovett M, Valentine MB, Look AT, Gerald W, Housman DE, Haber DA (1998) Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proc Natl Acad Sci USA 95:13765–13770

    Article  CAS  PubMed  Google Scholar 

  • Nichols KE, Hom J, Gong SY, Ganguly A, Ma CS, Cannons JL, Tangye SG, Schwartzberg PL, Koretzky GA, Stein PL (2005) Regulation of NKT cell development by SAP, the protein defective in XLP. Nat Med 11:340–345

    Article  CAS  PubMed  Google Scholar 

  • Nishizawa K, Freund C, Li J, Wagner G, Reinherz EL (1998) Identification of a proline-binding motif regulating CD2-triggered T lymphocyte activation. Proc Natl Acad Sci USA 95:14897–14902

    Article  CAS  PubMed  Google Scholar 

  • Parolini S, Bottino C, Falco M, Augugliaro R, Giliani S, Franceschini R, Ochs HD, Wolf H, Bonnefoy JY, Biassoni R, Moretta L, Notarangelo LD, Moretta A (2000) X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells. J Exp Med 192:337–346

    Article  CAS  PubMed  Google Scholar 

  • Pasquier B, Yin L, Fondaneche MC, Relouzat F, Bloch-Queyrat C, Lambert N, Fischer A, de Saint-Basile G, Latour S (2005) Defective NKT cell development in mice and humans lacking the adapter SAP, the X-linked lymphoproliferative syndrome gene product. J Exp Med 201:695–701

    Article  CAS  PubMed  Google Scholar 

  • Peck SR, Ruley HE (2000) Ly108: a newmember of the mouse CD2 family of cell surface proteins. Immunogenetics 52:63–72

    Article  CAS  PubMed  Google Scholar 

  • Pende D, Spaggiari GM, Marcenaro S, Martini S, Rivera P, Capobianco A, Falco M, Lanino E, Pierri I, Zambello R, Bacigalupo A, Mingari MC, Moretta A, Moretta L (2005) Analysis of the receptor-ligand interactions in the natural killer-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the Poliovirus receptor (CD155) and Nectin-2 (CD112). Blood 105:2066–2073

    Article  CAS  PubMed  Google Scholar 

  • Punnonen J, de Vries JE (1993) Characterization of a novel CD2+ human thymic B cell subset. J Immunol 151:100–110

    CAS  PubMed  Google Scholar 

  • Purtilo DT, Cassel CK, Yang JP, Harper R (1975) X-linked recessive progressive combined variable immunodeficiency (Duncan’s disease). Lancet 1:935–940

    Article  CAS  PubMed  Google Scholar 

  • Romero X, Benitez D, March S, Vilella R, Miralpeix M, Engel P (2004) Differential expression of SAP and EAT-2-binding leukocyte cell-surface molecules CD84, CD150 (SLAM), CD229 (Ly9) and CD244 (2B4). Tissue Antigens 64:132–144

    Article  CAS  PubMed  Google Scholar 

  • Romero X, Zapater N, Calvo M, Kalko SG, de la Fuente MA, Tovar V, Ockeloen C, Pizcueta P, Engel P (2005) CD229 (Ly9) lymphocyte cell surface receptor interacts homophilically through its N-terminal domain and relocalizes to the immunological synapse. J Immunol 174:7033–7042

    CAS  PubMed  Google Scholar 

  • Sandrin MS, Gumley TP, Henning MM, Vaughan HA, Gonez LJ, Trapani JA, McKenzie IF (1992) Isolation and characterization of cDNA clones for mouse Ly-9. J Immunol 149:1636–1641

    CAS  PubMed  Google Scholar 

  • Sayos J, Martin M, Chen A, Simarro M, Howie D, Morra M, Engel P, Terhorst C (2001) Cell surface receptors Ly-9 and CD84 recruit the X-linked lymphoproliferative disease gene product SAP. Blood 97:3867–3874

    Article  CAS  PubMed  Google Scholar 

  • Sayos J, Nguyen KB, Wu C, Stepp SE, Howie D, Schatzle JD, Kumar V, Biron CA, Terhorst C (2000) Potential pathways for regulation of NK and T cell responses: differential X-linked lymphoproliferative syndrome gene product SAP interactions with SLAM and 2B4. Int Immunol 12:1749–1757

    Article  CAS  PubMed  Google Scholar 

  • Sayos J, Wu C, Morra M, Wang N, Zhang X, Allen D, van Schaik S, Notarangelo L, Geha R, Roncarolo MG, Oettgen H, De Vries JE, Aversa G, Terhorst C (1998) The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395:462–469

    Article  CAS  PubMed  Google Scholar 

  • Schatzle JD, Sheu S, Stepp SE, Mathew PA, Bennett M, Kumar V (1999) Characterization of inhibitory and stimulatory forms of the murine natural killer cell receptor 2B4. Proc Natl Acad Sci USA 96:3870–3875

    Article  CAS  PubMed  Google Scholar 

  • Schmidt RE, Caulfield JP, Michon J, Hein A, Kamada MM, MacDermott RP, Stevens RL, Ritz J (1988) T11/CD2 activation of cloned human natural killer cells results in increased conjugate formation and exocytosis of cytolytic granules. J Immunol 140:991–1002

    CAS  PubMed  Google Scholar 

  • Schmidt RE, Michon JM, Woronicz J, Schlossman SF, Reinherz EL, Ritz J (1987) Enhancement of natural killer function through activation of the T11 E rosette receptor. J Clin Invest 79:305–308

    Article  CAS  PubMed  Google Scholar 

  • Seaman WE, Eriksson E, Dobrow R, Imboden JB (1987) Inositol trisphosphate is generated by a rat natural killer cell tumor in response to target cells or to crosslinked monoclonal antibody OX-34: possible signaling role for the OX-34 determinant during activation by target cells. Proc Natl Acad Sci USA 84:4239–4243

    CAS  PubMed  Google Scholar 

  • Senkevich TG, Koonin EV, Bugert JJ, Darai G, Moss B (1997) The genome of molluscum contagiosum virus: analysis and comparison with other poxviruses. Virology 233:19–42

    Article  CAS  PubMed  Google Scholar 

  • Shimizu Y, Mobley JL, Finkelstein LD, Chan AS (1995) A role for phosphatidylinositol 3-kinase in the regulation of β1 integrin activity by the CD2 antigen. J Cell Biol 131:1867–1880

    Article  CAS  PubMed  Google Scholar 

  • Shlapatska LM, Mikhalap SV, Berdova AG, Zelensky OM, Yun TJ, Nichols KE, Clark EA, Sidorenko SP (2001) CD150 association with either the SH2-containing inositol phosphatase or the SH2-containing protein tyrosine phosphatase is regulated by the adaptor protein SH2D1A. J Immunol 166:5480–5487

    CAS  PubMed  Google Scholar 

  • Sidorenko SP, Clark EA (1993) Characterization of a cell surface glycoprotein IPO-3, expressed on activated human B and T lymphocytes. J Immunol 151:4614–4624

    CAS  PubMed  Google Scholar 

  • Sidorenko SP, Clark EA (2003) The dual-function CD150 receptor subfamily: the viral attraction. Nat Immunol 4:19–24

    Article  CAS  PubMed  Google Scholar 

  • Siliciano RF, Pratt JC, Schmidt RE, Ritz J, Reinherz EL (1985) Activation of cytolytic T lymphocyte and natural killer cell function through the T11 sheep erythrocyte binding protein. Nature 317:428–430

    Article  CAS  PubMed  Google Scholar 

  • Simarro M, Lanyi A, Howie D, Poy F, Bruggeman J, Choi M, Sumegi J, Eck MJ, Terhorst C (2004) SAP increases FynT kinase activity and is required for phosphorylation of SLAM and Ly9. Int Immunol 16:727–736

    Article  CAS  PubMed  Google Scholar 

  • Sivori S, Falco M, Marcenaro E, Parolini S, Biassoni R, Bottino C, Moretta L, Moretta A (2002) Early expression of triggering receptors and regulatory role of 2B4 in human natural killer cell precursors undergoing in vitro differentiation. Proc Natl Acad Sci USA 99:4526–4531

    Article  CAS  PubMed  Google Scholar 

  • Sivori S, Parolini S, Falco M, Marcenaro E, Biassoni R, Bottino C, Moretta L, Moretta A (2000) 2B4 functions as a co-receptor in humanNK cell activation. Eur J Immunol 30:787–793

    Article  CAS  PubMed  Google Scholar 

  • Smith GM, Biggs J, Norris B, Anderson-Stewart P, Ward R (1997) Detection of a soluble formof the leukocyte surface antigen CD48 in plasma and its elevation in patients with lymphoid leukemias and arthritis. J Clin Immunol 17: 502–509

    Article  CAS  PubMed  Google Scholar 

  • Smith ME, Thomas JA (1990) Cellular expression of lymphocyte function associated antigens and the intercellular adhesion molecule-1 in normal tissue. J Clin Pathol 43:893–900

    CAS  PubMed  Google Scholar 

  • Solomon KR, Rudd CE, Finberg RW (1996) The association between glycosylphosphatidylinositol-anchored proteins and heterotrimeric G protein αsubunits in lymphocytes. Proc Natl Acad Sci USA 93:6053–6058

    Article  CAS  PubMed  Google Scholar 

  • Springer TA, Dustin ML, Kishimoto TK, Marlin SD (1987) The lymphocyte function-associated LFA-1, CD2, and LFA-3 molecules: cell adhesion receptors of the immune system. Annu Rev Immunol 5:223–252

    Article  CAS  PubMed  Google Scholar 

  • Staunton DE, Fisher RC, LeBeau MM, Lawrence JB, Barton DE, Francke U, Dustin M, Thorley-Lawson DA (1989) Blast-1 possesses a glycosyl-phosphatidylinositol (GPI) membrane anchor, is related to LFA-3 and OX-45, and maps tochromosome 1q21-23. J Exp Med 169:1087–1099

    Article  CAS  PubMed  Google Scholar 

  • Stefanova I, Horejsi V, Ansotegui IJ, Knapp W, Stockinger H (1991) GPI-anchored cell-surface molecules complexed to protein tyrosine kinases. Science 254:1016–1019

    CAS  PubMed  Google Scholar 

  • Stepp SE, Schatzle JD, Bennett M, Kumar V, Mathew PA (1999) Gene structure of the murine NK cell receptor 2B4: presence of two alternatively spliced isoforms with distinct cytoplasmic domains. Eur J Immunol 29:2392–2399

    Article  CAS  PubMed  Google Scholar 

  • Tangye SG, Cherwinski H, Lanier LL, Phillips JH (2000a) 2B4-mediated activation of human natural killer cells. Mol Immunol 37:493–501

    Article  CAS  PubMed  Google Scholar 

  • Tangye SG, Lazetic S, Woollatt E, Sutherland GR, Lanier LL, Phillips JH (1999) Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP. J Immunol 162:6981–6985

    CAS  PubMed  Google Scholar 

  • Tangye SG, Nichols KE, Hare NJ, van de Weerdt BCM (2003) Functional requirements for interactions between CD84 and Src Homology 2 domain-containing proteins and their contribution to human T cell activation. J Immunol 171: 2485–2495

    CAS  PubMed  Google Scholar 

  • Tangye SG, Phillips JH, Lanier LL, Nichols KE (2000b) Functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome. J Immunol 165: 2932–2936

    CAS  PubMed  Google Scholar 

  • Tangye SG, van de Weerdt BC, Avery DT, Hodgkin PD (2002) CD84 is up-regulated on a major population of human memory B cells and recruits the SH2 domain containing proteins SAP and EAT-2. Eur J Immunol 32:1640–1649

    Article  CAS  PubMed  Google Scholar 

  • Tatsuo H, Ono N, Tanaka K, Yanagi Y (2000) SLAM (CDw150) is a cellular receptor for measles virus. Nature 406:893–897

    Article  CAS  PubMed  Google Scholar 

  • Teh S-J, Killeen N, Tarakhovsky A, Littman DR, Teh H-S (1997) CD2 regulates the positive selection and function of antigen-specific CD4-CD8+ T cells. Blood 89:1308–1318

    CAS  PubMed  Google Scholar 

  • Thompson AD, Braun BS, Arvand A, Stewart SD, May WA, Chen E, Korenberg J, Denny C (1996) EAT-2 is a novel SH2 domain containing protein that is up regulated by Ewing’s sarcoma EWS/FLI1 fusion gene. Oncogene 13: 2649–2658

    CAS  PubMed  Google Scholar 

  • Thorley-Lawson DA, Schooley RT, Bhan AK, Nadler LM (1982) Epstein-Barr virus superinduces a new human B cell differentiation antigen (B-LAST 1) expressed on transformed lymphoblasts. Cell 30:415–425

    Article  CAS  PubMed  Google Scholar 

  • Tibaldi EV, Reinherz EL (2003) CD2BP3, CIN85 and the structurally related adaptor protein CMS bind to the same CD2 cytoplasmic segment, but elicit divergent functional activities. Int Immunol 15:313–329

    Article  CAS  PubMed  Google Scholar 

  • Timonen T, Gahmberg CG, Patarroyo M (1990) Participation of CD11a-c/CD18, CD2 and RGD-binding receptors in endogenous and interleukin-2-stimulated NK activity of CD3-negative large granular lymphocytes. Int J Cancer 46: 1035–1040

    CAS  PubMed  Google Scholar 

  • Tovar V, de la Fuente MA, Pizcueta P, Bosch J, Engel P (2000) Gene structure of the mouse leukocyte cell surface molecule Ly9. Immunogenetics 51:788–793

    Article  CAS  PubMed  Google Scholar 

  • Tovar V, del Valle J, Zapater N, Martin M, Romero X, Pizcueta P, Bosch J, Terhorst C, Engel P (2002) Mouse novel Ly9: a new member of the expanding CD150 (SLAM) family of leukocyte cell-surface receptors. Immunogenetics 54:394–402

    Article  CAS  PubMed  Google Scholar 

  • Vaidya SV, Stepp SE, McNerney ME, Lee JK, Bennett M, Lee KM, Stewart CL, Kumar V, Mathew PA (2005) Targeted disruption of the 2B4 gene in mice reveals an in vivo role of 2B4 (CD244) in the rejection of B16 melanoma cells. J Immunol 174:800–807

    CAS  PubMed  Google Scholar 

  • Valdez PA, Wang H, Seshasayee D, van Lookeren Campagne M, Gurney A, Lee WP, Grewal IS (2004) NTB-A, a new activating receptor in T cells that regulates autoimmune disease. J Biol Chem 279:18662–18669

    Article  CAS  PubMed  Google Scholar 

  • Valiante NM, Trinchieri G (1993) Identification of a novel signal transduction surface molecule on human cytotoxic lymphocytes. J Exp Med 178:1397–1406

    Article  CAS  PubMed  Google Scholar 

  • van de Griend RJ, Bolhuis RL, Stoter G, Roozemond RC (1987) Regulation of cytolytic activity in CD3-and CD3+ killer cell clones by monoclonal antibodies (anti-CD16, anti-CD2, anti-CD3) depends on subclass specificity of target cell IgG-FcR. J Immunol 138:3137–3144

    PubMed  Google Scholar 

  • Vivier E, Morin PM, O’Brien C, Schlossman SF, Anderson P (1991) CD2 is functionally linked to the zeta-natural killer receptor complex. Eur J Immunol 21:1077–1080

    CAS  PubMed  Google Scholar 

  • Voltarelli JC, Gjerset G, Anasetti C (1993) Adhesion of CD16+ K cells to antibody-coated targets is mediated by CD2 and CD18 receptors. Immunology 79:509–511

    CAS  PubMed  Google Scholar 

  • Wandstrat AE, Nguyen C, Limaye N, Chan AY, Subramanian S, Tian XH, Yim YS, Pertsemlidis A, Garner HR, Jr., Morel L, Wakeland EK (2004) Association of extensive polymorphisms in the SLAM/CD2 gene cluster with murine lupus. Immunity 21:769–780

    Article  CAS  PubMed  Google Scholar 

  • Wang N, Morra M, Wu C, Gullo C, Howie D, Coyle T, Engel P, Terhorst C (2001) CD150 is a member of a family of genes that encode glycoproteins on the surface of hematopoietic cells. Immunogenetics 53:382–394

    Article  CAS  PubMed  Google Scholar 

  • Wang N, Satoskar A, Faubion W, Howie D, Okamoto S, Feske S, Gullo C, Clarke K, Sosa MR, Sharpe AH, Terhorst C (2004) The cell surface receptor SLAM controls T cell and macrophage functions. J Exp Med 199:1255–1264

    Article  CAS  PubMed  Google Scholar 

  • Watzl C, Stebbins CC, Long EO (2000) NK cell inhibitory receptors prevent tyrosine phosphorylation of the activation receptor 2B4 (CD244). J Immunol 165:3545–3548

    CAS  PubMed  Google Scholar 

  • Wong YW, Williams AF, Kingsmore SF, Seldin MF (1990) 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. J Exp Med 171:2115–2130

    Article  CAS  PubMed  Google Scholar 

  • Wu C, Nguyen KB, Pien GC, Wang N, Gullo C, Howie D, Sosa MR, Edwards MJ, Borrow P, Satoskar AR, Sharpe AH, Biron CA, Terhorst C (2001) SAP controls T cell responses to virus and terminal differentiation of TH2 cells. Nat Immunol 2:410–414

    Article  CAS  PubMed  Google Scholar 

  • Yagita H, Nakamura T, Karasuyama H, Okumura K (1989) Monoclonal antibodies specific for murine CD2 reveal its presence on B as well as T cells. Proc Natl Acad Sci USA 86:645–649

    CAS  PubMed  Google Scholar 

  • Yin L, Al-Alem U, Liang J, Tong WM, Li C, Badiali M, Medard JJ, Sumegi J, Wang ZQ, Romeo G (2003) Mice deficient in the X-linked lymphoproliferative disease gene sap exhibit increased susceptibility to murine gammaherpesvirus-68 and hypo-gammaglobulinemia. J Med Virol 71:446–455

    Article  CAS  PubMed  Google Scholar 

  • Zaiss M, Hirtreiter C, Rehli M, Rehm A, Kunz-Schughart LA, Andreesen R, Hennemann B (2003) CD84 expression on human hematopoietic progenitor cells. Exp Hematol 31:798–805

    Article  CAS  PubMed  Google Scholar 

  • Zhang W, Wan T, Li N, Yuan Z, He L, Zhu X, Yu M, Cao X (2001) Genetic approach to insight into the immunobiology of human dendritic cells and identification of CD84-H1, a novel CD84 homologue. Clin Cancer Res 7: 822s–829s

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Committee on Immunology, University of Chicago, 5841 S. Maryland Ave., S-315 MC3083, Chicago, IL, 60637, USA

    M. E. McNerney & V. Kumar

Authors
  1. M. E. McNerney
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Atlanta, Georgia

    R.W. Compans

  2. Birmingham, Alabama

    M.D. Cooper

  3. Kyoto

    T. Honjo

  4. Philadelphia, Pennsylvania

    H. Koprowski

  5. Basel

    F. Melchers

  6. La Jolla, California

    M.B.A. Oldstone

  7. Oslo

    S. Olsnes

  8. Bethesda, Maryland

    M. Potter

  9. La Jolla, California

    P.K. Vogt

  10. Munich

    H. Wagner

  11. Laboratory of NK Cells and Innate Immunity, Centre d’Immunologie de Marseille-Luminy (CIML), CNRS-INSERM-Université de la Méditerranée, Campus de Luminy, Case 906, 13288, Marseille Cedex 09, France

    Eric Vivier DVM, PhD.

  12. Department of Pathology and Immunology, Washington University School of Medicine, West Building, Rooms 4724, Box 8118 660 South Euclid Ave, St. Louis, MO, 63110, USA

    Marco Colonna M.D.

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

McNerney, M.E., Kumar, V. (2006). The CD2 Family of Natural Killer Cell Receptors. In: Compans, R., et al. Immunobiology of Natural Killer Cell Receptors. Current Topics in Microbiology and Immunology, vol 298. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-27743-9_5

Download citation

Publish with us

Policies and ethics

Search

Navigation