Skip to main content

Advertisement

SpringerLink
Log in

Leukocyte integrins and their ligand interactions

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Although critical for cell adhesion and migration during normal immune-mediated reactions, leukocyte integrins are also involved in the pathogenesis of diverse clinical conditions including autoimmune diseases and chronic inflammation. Leukocyte integrins therefore have been targets for anti-adhesive therapies to treat the inflammatory disorders. Recently, the therapeutic potential of integrin antagonists has been demonstrated in psoriasis and multiple sclerosis. However, current therapeutics broadly affect integrin functions and, thus, yield unfavorable side effects. This review discusses the major leukocyte integrins and the anti-adhesion strategies for treating immune diseases.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multi-step paradigm. Cell. 1994;76:301–14.

    PubMed  CAS  Google Scholar 

  2. Shimaoka M, Springer TA. Therapeutic antagonists and the conformational regulation of integrin structure and function. Nat Rev Drug Discov. 2003;2:703–16.

    PubMed  CAS  Google Scholar 

  3. Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, et al. The immunological synapse: a molecular machine controlling T cell activation. Science. 1999;285:221–7.

    PubMed  CAS  Google Scholar 

  4. Ulyanova T, Priestley GV, Banerjee ER, Papayannopoulou T. Unique and redundant roles of alpha4 and beta2 integrins in kinetics of recruitment of lymphoid vs myeloid cell subsets to the inflamed peritoneum revealed by studies of genetically deficient mice. Exp Hematol. 2007;35:1256–65.

    PubMed  CAS  Google Scholar 

  5. Ghosh S, Chackerian AA, Parker CM, Ballantyne CM, Behar SM. The LFA-1 adhesion molecule is required for protective immunity during pulmonary Mycobacterium tuberculosis infection. J Immunol. 2006;176:4914–22.

    PubMed  CAS  Google Scholar 

  6. Marlin SD, Springer TA. Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1). Cell. 1987;51:813–9.

    PubMed  CAS  Google Scholar 

  7. de Fougerolles AR, Stacker SA, Schwarting R, Springer TA. Characterization of ICAM-2 and evidence for a third counter-receptor for LFA-1. J Exp Med. 1991;174:253–67.

    PubMed  Google Scholar 

  8. de Fougerolles AR, Qin X, Springer TA. Characterization of the function of ICAM-3 and comparison to ICAM-1 and ICAM-2 in immune responses. J Exp Med. 1994;179:619–29.

    PubMed  Google Scholar 

  9. Tian L, Kilgannon P, Yoshihara Y, Mori K, Gallatin WM, Carpen O, et al. Binding of T lymphocytes to hippocampal neurons through ICAM-5 (telencephalin) and characterization of its interaction with the leukocyte integrin CD11a/CD18. Eur J Immunol. 2000;30:810–8.

    PubMed  CAS  Google Scholar 

  10. Ihanus E, Uotila L, Toivanen A, Stefanidakis M, Bailly P, Cartron JP, et al. Characterization of ICAM-4 binding to the I domains of the CD11a/CD18 and CD11b/CD18 leukocyte integrins. Eur J Biochem. 2003;270:1710–23.

    PubMed  CAS  Google Scholar 

  11. Ostermann G, Weber KS, Zernecke A, Schroder A, Weber C. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol. 2002;3:151–8.

    PubMed  CAS  Google Scholar 

  12. Wang J, Springer TA. Structural specializations of immunoglobulin superfamily members for adhesion to integrins and viruses. Immunol Rev. 1998;163:197–215.

    PubMed  CAS  Google Scholar 

  13. Shimaoka M, Xiao T, Liu J-H, Yang Y, Dong Y, Jun C-D, et al. Structures of the αL I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation. Cell. 2003;112:99–111.

    PubMed  CAS  Google Scholar 

  14. van Seventer G, Shimizu Y, Horgan K, Shaw S. The LFA-1 ligand ICAM-1 provides an important costimulatory signal for T cell receptor-mediated activation of resting T cells. J Immunol. 1990;144:4579–86.

    PubMed  Google Scholar 

  15. Mallinson G, Martin PG, Anstee DJ, Tanner MJ, Merry AH, Tills D, et al. Identification and partial characterization of the human erythrocyte membrane component(s) that express the antigens of the LW blood-group system. Biochem J. 1986;234:649–52.

    PubMed  CAS  Google Scholar 

  16. Katagiri K, Hattori M, Minato N, Irie S, Takatsu K, Kinashi T. Rap1 is a potent activation signal for leukocyte function-associated antigen 1 distinct from protein kinase C and phosphatidylinositol-3-OH kinase. Mol Cell Biol. 2000;20:1956–69.

    PubMed  CAS  Google Scholar 

  17. Kawasaki H, Springett GM, Toki S, Canales JJ, Harlan P, Blumenstiel JP, et al. A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia. Proc Natl Acad Sci USA. 1998;95:13278–83.

    PubMed  CAS  Google Scholar 

  18. Crittenden JR, Bergmeier W, Zhang Y, Piffath CL, Liang Y, Wagner DD, et al. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nat Med. 2004;10:982–6.

    PubMed  CAS  Google Scholar 

  19. Ghandour H, Cullere X, Alvarez A, Luscinskas FW, Mayadas TN. Essential role for Rap1 GTPase and its guanine exchange factor CalDAG-GEFI in LFA-1 but not VLA-4 integrin mediated human T-cell adhesion. Blood. 2007;110:3682–90.

    PubMed  CAS  Google Scholar 

  20. Pasvolsky R, Feigelson SW, Kilic SS, Simon AJ, Tal-Lapidot G, Grabovsky V, et al. A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J Exp Med. 2007;204:1571–82.

    PubMed  CAS  Google Scholar 

  21. Kinashi T, Katagiri K. Regulation of lymphocyte adhesion and migration by the small GTPase Rap1 and its effector molecule, RAPL. Immunol Lett. 2004;93:1–5.

    PubMed  CAS  Google Scholar 

  22. Katagiri K, Imamura M, Kinashi T. Spatiotemporal regulation of the kinase Mst1 by binding protein RAPL is critical for lymphocyte polarity and adhesion. Nat Immunol. 2006;7:919–28.

    PubMed  CAS  Google Scholar 

  23. Katagiri K, Maeda A, Shimonaka M, Kinashi T. RAPL, a novel Rap1-binding molecule, mediates Rap1-induced adhesion through spatial regulation of LFA-1. Nat Immunol. 2003;4:741–8.

    PubMed  CAS  Google Scholar 

  24. Katagiri K, Ohnishi N, Kabashima K, Iyoda T, Takeda N, Shinkai Y, et al. Crucial functions of the Rap1 effector molecule RAPL in lymphocyte and dendritic cell trafficking. Nat Immunol. 2004;5:1045–51.

    PubMed  CAS  Google Scholar 

  25. Lafuente EM, van Puijenbroek AA, Krause M, Carman CV, Freeman GJ, Berezovskaya A, et al. RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesion. Dev Cell. 2004;7:585–95.

    PubMed  CAS  Google Scholar 

  26. Rose DM, Alon R, Ginsberg MH. Integrin modulation and signaling in leukocyte adhesion and migration. Immunol Rev. 2007;218:126–34.

    PubMed  CAS  Google Scholar 

  27. Li X, Bu X, Lu B, Avraham H, Flavell RA, Lim B. The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function. Mol Cell Biol. 2002;22:1158–71.

    PubMed  CAS  Google Scholar 

  28. Cherry LK, Li X, Schwab P, Lim B, Klickstein LB. RhoH is required to maintain the integrin LFA-1 in a nonadhesive state on lymphocytes. Nat Immunol. 2004;5:961–7.

    PubMed  CAS  Google Scholar 

  29. Bianchi E, Denti S, Granata A, Bossi G, Geginat J, Villa A, et al. Integrin LFA-1 interacts with the transcriptional co-activator JAB1 to modulate AP-1 activity. Nature. 2000;404:617–21.

    PubMed  CAS  Google Scholar 

  30. Kolanus W, Nagel W, Schiller B, Zeitlmann L, Godar S, Stockinger H, et al. αLβ2 integrin/LFA-1 binding to ICAM-1 induced by cytohesin-1, a cytoplasmic regulatory molecule. Cell. 1996;86:233–42.

    PubMed  CAS  Google Scholar 

  31. Weber KS, Weber C, Ostermann G, Dierks H, Nagel W, Kolanus W. Cytohesin-1 is a dynamic regulator of distinct LFA-1 functions in leukocyte arrest and transmigration triggered by chemokines. Curr Biol. 2001;11:1969–74.

    PubMed  CAS  Google Scholar 

  32. Mor A, Dustin ML, Philips MR. Small GTPases and LFA-1 reciprocally modulate adhesion and signaling. Immunol Rev. 2007;218:114–25.

    PubMed  CAS  Google Scholar 

  33. Perez OD, Mitchell D, Jager GC, South S, Murriel C, McBride J, et al. Leukocyte functional antigen 1 lowers T cell activation thresholds and signaling through cytohesin-1 and Jun-activating binding protein 1. Nat Immunol. 2003;4:1083–92.

    PubMed  CAS  Google Scholar 

  34. Bresnick AR. Molecular mechanisms of nonmuscle myosin-II regulation. Curr Opin Cell Biol. 1999;11:26–33.

    PubMed  CAS  Google Scholar 

  35. Berg JS, Powell BC, Cheney RE. A millennial myosin census. Mol Biol Cell. 2001;12:780–94.

    PubMed  CAS  Google Scholar 

  36. Morin NA, Oakes PW, Hyun YM, Lee D, Chin EY, King MR, et al. Nonmuscle myosin heavy chain IIAmediates integrin LFA-1 de-adhesion during T lymphocyte migration. J Exp Med. 2008;205:195–205.

    PubMed  CAS  Google Scholar 

  37. Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med. 2003;349:2004–13.

    PubMed  CAS  Google Scholar 

  38. Simmons DL. Anti-adhesion therapies. Curr Opin Pharmacol. 2005;5:398–404.

    PubMed  CAS  Google Scholar 

  39. Gauvreau GM, Becker AB, Boulet LP, Chakir J, Fick RB, Greene WL, et al. The effects of an anti-CD11a mAb, efalizumab, on allergen-induced airway responses and airway inflammation in subjects with atopic asthma. J Allergy Clin Immunol. 2003;112:331–8.

    PubMed  CAS  Google Scholar 

  40. Fischer A, Friedrich W, Fasth A, Blanche S, Le Deist F, Girault D, et al. Reduction of graft failure by a monoclonal antibody (anti-LFA-1 CD11a) after HLA nonidentical bone marrow transplantation in children with immunodeficiencies, osteopetrosis, and Fanconi’s anemia: a European Group for immunodeficiency/European Group for bone marrow transplantation report. Blood. 1991;77:249–56.

    PubMed  CAS  Google Scholar 

  41. Gonzalez-Amaro R, Mittelbrunn M, Sanchez-Madrid F. Therapeutic anti-integrin (alpha4 and alphaL) monoclonal antibodies: two-edged swords? Immunology. 2005;116:289–96.

    PubMed  CAS  Google Scholar 

  42. Le Mauff B, Hourmant M, Rougier JP, Hirn M, Dantal J, Baatard R, et al. Effect of anti-LFA1 (CD11a) monoclonal antibodies in acute rejection in human kidney transplantation. Transplantation. 1991;52:291–6.

    Article  PubMed  CAS  Google Scholar 

  43. Stoppa AM, Maraninchi D, Blaise D, Viens P, Hirn M, Olive D, et al. Anti-LFA1 monoclonal antibody (25.3) for treatment of steroid-resistant grade III-IV acute graft-versus-host disease. Transpl Int. 1991;4:3–7.

    PubMed  CAS  Google Scholar 

  44. Cantor JM, Ginsberg MH, Rose DM. Integrin-associated proteins as potential therapeutic targets. Immunol Rev. 2008;223:236–51.

    PubMed  CAS  Google Scholar 

  45. Springer T, Galfre G, Secher DS, Milstein C. Mac-1: a macrophage differentiation antigen identified by monoclonal antibody. Eur J Immunol. 1979;9:301–6.

    PubMed  CAS  Google Scholar 

  46. Plow EF, Zhang L. A MAC-1 attack: integrin functions directly challenged in knockout mice. J Clin Invest. 1997;99:1145–6.

    PubMed  CAS  Google Scholar 

  47. McFarland HI, Nahill SR, Maciaszek JW, Welsh RM. CD11b (Mac-1): a marker for CD8+ cytotoxic T cell activation and memory in virus infection. J Immunol. 1992;149:1326–33.

    PubMed  CAS  Google Scholar 

  48. Springer TA, Thompson WS, Miller LJ, Schmalstieg FC, Anderson DC. Inherited deficiency of the Mac-1, LFA-1, p150, 95 glycoprotein family and its molecular basis. J Exp Med. 1984;160:1901–18.

    PubMed  CAS  Google Scholar 

  49. Miller LJ, Bainton DF, Borregaard N, Springer TA. Stimulated mobilization of monocyte Mac-1 and p150, 95 adhesion proteins from an intracellular vesicular compartment to the cell surface. J Clin Invest. 1987;80:535–44.

    PubMed  CAS  Google Scholar 

  50. Todd RF III, Arnaout MA, Rosin RE, Crowley CA, Peters WA, Babior BM. Subcellular localization of the large subunit of Mo1 (Mo1 alpha; formerly gp 110), a surface glycoprotein associated with neutrophil adhesion. J Clin Invest. 1984;74:1280–90.

    PubMed  CAS  Google Scholar 

  51. Vedder NB, Harlan JM. Increased surface expression of CD11b/CD18 (Mac-1) is not required for stimulated neutrophil adherence to cultured endothelium. J Clin Invest. 1988;81:676–82.

    PubMed  CAS  Google Scholar 

  52. Diamond MS, Springer TA. A subpopulation of Mac-1 (CD11b/CD18) molecules mediates neutrophil adhesion to ICAM-1 and fibrinogen. J Cell Biol. 1993;120:545–56.

    PubMed  CAS  Google Scholar 

  53. Davey PC, Zuzel M, Kamiguti AS, Hunt JA, Aziz KA. Activation-dependent proteolytic degradation of polymorphonuclear CD11b. Br J Haematol. 2000;111:934–42.

    PubMed  CAS  Google Scholar 

  54. Phillipson M, Heit B, Colarusso P, Liu L, Ballantyne CM, Kubes P. Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J Exp Med. 2006;203:2569–75.

    PubMed  CAS  Google Scholar 

  55. Diamond MS, Garcia-Aguilar J, Bickford JK, Corbi AL, Springer TA. The I domain is a major recognition site on the leukocyte integrin Mac-1 (CD11b/CD18) for four distinct adhesion ligands. J Cell Biol. 1993;120:1031–43.

    PubMed  CAS  Google Scholar 

  56. Diamond MS, Staunton DE, de Fougerolles AR, Stacker SA, Garcia-Aguilar J, Hibbs ML, et al. ICAM-1 (CD54): a counter-receptor for Mac-1 (CD11b/CD18). J Cell Biol. 1990;111:3129–39.

    PubMed  CAS  Google Scholar 

  57. Gahmberg CG. Leukocyte adhesion: CD11/CD18 integrins and intercellular adhesion molecules. Curr Opin Cell Biol. 1997;9:643–50.

    PubMed  CAS  Google Scholar 

  58. Altieri DC, Bader R, Mannucci PM, Edgington TS. Oligospecificity of the cellular adhesion receptor Mac-1 encompasses an inducible recognition specificity for fibrinogen. J Cell Biol. 1988;107:1893–900.

    PubMed  CAS  Google Scholar 

  59. Beller DI, Springer TA, Schreiber RD. Anti-Mac-1 selectively inhibits the mouse and human type three complement receptor. J Exp Med. 1982;156:1000–9.

    PubMed  CAS  Google Scholar 

  60. Ehlers MR. CR3: a general purpose adhesion-recognition receptor essential for innate immunity. Microbes Infect. 2000;2:289–94.

    PubMed  CAS  Google Scholar 

  61. Diamond MS, Staunton DE, Marlin SD, Springer TA. Binding of the integrin Mac-1 (CD11b/CD18) to the third immunoglobulin-like domain of ICAM-1 (CD54) and its regulation by glycosylation. Cell. 1991;65:961–71.

    PubMed  CAS  Google Scholar 

  62. Lub M, van Kooyk Y, Figdor CG. Competition between lymphocyte function-associated antigen 1 (CD11a/CD18) and Mac-1 (CD11b/CD18) for binding to intercellular adhesion molecule-1 (CD54). J Leukoc Biol. 1996;59:648–55.

    PubMed  CAS  Google Scholar 

  63. Ding ZM, Babensee JE, Simon SI, Lu H, Perrard JL, Bullard DC, et al. Relative contribution of LFA-1 and Mac-1 to neutrophil adhesion and migration. J Immunol. 1999;163:5029–38.

    PubMed  CAS  Google Scholar 

  64. Yakubenko VP, Lishko VK, Lam SC, Ugarova TP. A molecular basis for integrin alphaMbeta 2 ligand binding promiscuity. J Biol Chem. 2002;277:48635–42.

    PubMed  CAS  Google Scholar 

  65. Zhang L, Plow EF. Amino acid sequences within the alpha subunit of integrin alpha M beta 2 (Mac-1) critical for specific recognition of C3bi. Biochemistry. 1999;38:8064–71.

    PubMed  CAS  Google Scholar 

  66. Weber KS, Klickstein LB, Weber C. Specific activation of leukocyte beta2 integrins lymphocyte function-associated antigen-1 and Mac-1 by chemokines mediated by distinct pathways via the alpha subunit cytoplasmic domains. Mol Biol Cell. 1999;10:861–73.

    PubMed  CAS  Google Scholar 

  67. Heit B, Colarusso P, Kubes P. Fundamentally different roles for LFA-1, Mac-1 and alpha4-integrin in neutrophil chemotaxis. J Cell Sci. 2005;118:5205–20.

    PubMed  CAS  Google Scholar 

  68. Fagerholm SC, Hilden TJ, Nurmi SM, Gahmberg CG. Specific integrin alpha and beta chain phosphorylations regulate LFA-1 activation through affinity-dependent and -independent mechanisms. J Cell Biol. 2005;171:705–15.

    PubMed  CAS  Google Scholar 

  69. Fagerholm SC, Varis M, Stefanidakis M, Hilden TJ, Gahmberg CG. alpha-Chain phosphorylation of the human leukocyte CD11b/CD18 (Mac-1) integrin is pivotal for integrin activation to bind ICAMs and leukocyte extravasation. Blood. 2006;108:3379–86.

    PubMed  CAS  Google Scholar 

  70. Muchowski PJ, Zhang L, Chang ER, Soule HR, Plow EF, Moyle M. Functional interaction between the integrin antagonist neutrophil inhibitory factor and the I domain of CD11b/CD18. J Biol Chem. 1994;269:26419–23.

    PubMed  CAS  Google Scholar 

  71. Jiang N, Chopp M, Chahwala S. Neutrophil inhibitory factor treatment of focal cerebral ischemia in the rat. Brain Res. 1998;788:25–34.

    PubMed  CAS  Google Scholar 

  72. Krams M, Lees KR, Hacke W, Grieve AP, Orgogozo JM, Ford GA. Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279, 276 in acute ischemic stroke. Stroke. 2003;34:2543–8.

    PubMed  CAS  Google Scholar 

  73. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC investigation. N Engl J Med. 1994;330:956–61.

  74. Tcheng JE, Kandzari DE, Grines CL, Cox DA, Effron MB, Garcia E, et al. Benefits and risks of abciximab use in primary angioplasty for acute myocardial infarction: the controlled abciximab and device investigation to lower late angioplasty complications (CADILLAC) trial. Circulation. 2003;108:1316–23.

    PubMed  CAS  Google Scholar 

  75. Anderson KM, Califf RM, Stone GW, Neumann FJ, Montalescot G, Miller DP, et al. Long-term mortality benefit with abciximab in patients undergoing percutaneous coronary intervention. J Am Coll Cardiol. 2001;37:2059–65.

    PubMed  CAS  Google Scholar 

  76. Inoue T, Sakai Y, Fujito T, Hoshi K, Hayashi T, Takayanagi K, et al. Clinical significance of neutrophil adhesion molecules expression after coronary angioplasty on the development of restenosis. Thromb Haemost. 1998;79:54–8.

    PubMed  CAS  Google Scholar 

  77. Pietersma A, Kofflard M, de Wit LE, Stijnen T, Koster JF, Serruys PW, et al. Late lumen loss after coronary angioplasty is associated with the activation status of circulating phagocytes before treatment. Circulation. 1995;91:1320–5.

    PubMed  CAS  Google Scholar 

  78. Mickelson JK, Lakkis NM, Villarreal-Levy G, Hughes BJ, Smith CW. Leukocyte activation with platelet adhesion after coronary angioplasty: a mechanism for recurrent disease? J Am Coll Cardiol. 1996;28:345–53.

    PubMed  CAS  Google Scholar 

  79. Schwarz M, Nordt T, Bode C, Peter K. The GP IIb/IIIa inhibitor abciximab (c7E3) inhibits the binding of various ligands to the leukocyte integrin Mac-1 (CD11b/CD18, alphaMbeta2). Thromb Res. 2002;107:121–8.

    PubMed  CAS  Google Scholar 

  80. Rogers C, Edelman ER, Simon DI. A mAb to the beta2-leukocyte integrin Mac-1 (CD11b/CD18) reduces intimal thickening after angioplasty or stent implantation in rabbits. Proc Natl Acad Sci USA. 1998;95:10134–9.

    PubMed  CAS  Google Scholar 

  81. Ross GD, Cain JA, Myones BL, Newman SL, Lachmann PJ. Specificity of membrane complement receptor type three (CR3) for beta-glucans. Complement. 1987;4:61–74.

    PubMed  CAS  Google Scholar 

  82. Thornton BP, Vetvicka V, Pitman M, Goldman RC, Ross GD. Analysis of the sugar specificity and molecular location of the β-glucan-binding lectin site of complement receptor type 3 (CD11b/CD18). J Immunol. 1996;156:1235–46.

    PubMed  CAS  Google Scholar 

  83. Xia Y, Vetvicka V, Yan J, Hanikyrova M, Mayadas T, Ross GD. The beta-glucan-binding lectin site of mouse CR3 (CD11b/CD18) and its function in generating a primed state of the receptor that mediates cytotoxic activation in response to iC3b-opsonized target cells. J Immunol. 1999;162:2281–90.

    PubMed  CAS  Google Scholar 

  84. Hong F, Hansen RD, Yan J, Allendorf DJ, Baran JT, Ostroff GR, et al. Beta-glucan functions as an adjuvant for monoclonal antibody immunotherapy by recruiting tumoricidal granulocytes as killer cells. Cancer Res. 2003;63:9023–31.

    PubMed  CAS  Google Scholar 

  85. Yan J, Vetvicka V, Xia Y, Coxon A, Carroll MC, Mayadas TN, et al. Beta-glucan, a “specific” biologic response modifier that uses antibodies to target tumors for cytotoxic recognition by leukocyte complement receptor type 3 (CD11b/CD18). J Immunol. 1999;163:3045–52.

    PubMed  CAS  Google Scholar 

  86. Eisenhardt SU, Schwarz M, Schallner N, Soosairajah J, Bassler N, Huang D, et al. Generation of activation-specific human anti-alphaMbeta2 single-chain antibodies as potential diagnostic tools and therapeutic agents. Blood. 2007;109:3521–8.

    PubMed  CAS  Google Scholar 

  87. Lobb RR, Hemler ME. The pathophysiologic role of alpha 4 integrins in vivo. J Clin Invest. 1994;94:1722–8.

    PubMed  CAS  Google Scholar 

  88. Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol. 2007;25:619–47.

    PubMed  CAS  Google Scholar 

  89. Puig-Kroger A, Sanz-Rodriguez F, Longo N, Sanchez-Mateos P, Botella L, Teixido J, et al. Maturation-dependent expression and function of the CD49d integrin on monocyte-derived human dendritic cells. J Immunol. 2000;165:4338–45.

    PubMed  CAS  Google Scholar 

  90. Rosen GD, Sanes JR, LaChance R, Cunningham JM, Roman J, Dean DC. Roles for the integrin VLA-4 and its counter receptor VCAM-1 in myogenesis. Cell. 1992;69:1107–19.

    PubMed  CAS  Google Scholar 

  91. Nieto M, Gomez M, Sanchez-Mateos P, Fernandez E, Marazuela M, Sacedon R, et al. Expression of functionally active alpha 4 beta 1 integrin by thymic epithelial cells. Clin Exp Immunol. 1996;106:170–8.

    PubMed  CAS  Google Scholar 

  92. Prosper F, Stroncek D, McCarthy JB, Verfaillie CM. Mobilization and homing of peripheral blood progenitors is related to reversible downregulation of alpha4 beta1 integrin expression and function. J Clin Invest. 1998;101:2456–67.

    PubMed  CAS  Google Scholar 

  93. Yang JT, Rayburn H, Hynes RO. Cell adhesion events mediated by α4 integrins are essential in placental and cardiac development. Development. 1995;121:549–60.

    PubMed  CAS  Google Scholar 

  94. Cunningham SA, Rodriguez JM, Arrate MP, Tran TM, Brock TA. JAM2 interacts with alpha4beta1. Facilitation by JAM3. J Biol Chem. 2002;277:27589–92.

    PubMed  CAS  Google Scholar 

  95. Ebnet K, Suzuki A, Ohno S, Vestweber D. Junctional adhesion molecules (JAMs): more molecules with dual functions? J Cell Sci. 2004;117:19–29.

    PubMed  CAS  Google Scholar 

  96. Butcher EC, Williams M, Youngman K, Rott L, Briskin M. Lymphocyte trafficking and regional immunity. Adv Immunol. 1999;72:209–53.

    PubMed  CAS  Google Scholar 

  97. Alon R, Kassner PD, Carr MW, Finger EB, Hemler ME, Springer TA. The integrin VLA-4 supports tethering and rolling in flow on VCAM-1. J Cell Biol. 1995;128:1243–53.

    PubMed  CAS  Google Scholar 

  98. Berlin C, Bargatze RF, von Andrian UH, Szabo MC, Hasslen SR, Nelson RD, et al. α4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell. 1995;80:413–22.

    PubMed  CAS  Google Scholar 

  99. Sims TN, Dustin ML. The immunological synapse: integrins take the stage. Immunol Rev. 2002;186:100–17.

    PubMed  CAS  Google Scholar 

  100. Mittelbrunn M, Molina A, Escribese MM, Yanez-Mo M, Escudero E, Ursa A, et al. VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses. Proc Natl Acad Sci USA. 2004;101:11058–63.

    PubMed  CAS  Google Scholar 

  101. Reedquist KA, Ross E, Koop EA, Wolthuis RM, Zwartkruis FJ, van Kooyk Y, et al. The small GTPase, Rap1, mediates CD31-induced integrin adhesion. J Cell Biol. 2000;148:1151–8.

    PubMed  CAS  Google Scholar 

  102. Bos JL, de Rooij J, Reedquist KA. Rap1 signalling: adhering to new models. Nat Rev Mol Cell Biol. 2001;2:369–77.

    PubMed  CAS  Google Scholar 

  103. Goldfinger LE, Han J, Kiosses WB, Howe AK, Ginsberg MH. Spatial restriction of α4 integrin phosphorylation regulates lamellipodial stability and α4β1-dependent cell migration. J Cell Biol. 2003;162:731–41.

    PubMed  CAS  Google Scholar 

  104. Han J, Rose DM, Woodside DG, Goldfinger LE, Ginsberg MH. Integrin α4β1-dependent cell migration requires both phosphorylation and de-phosphorylation of the a4 cytoplasmic domain. J Biol Chem. 2003;278:34845–53.

    PubMed  CAS  Google Scholar 

  105. Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature. 1992;356:63–6.

    PubMed  CAS  Google Scholar 

  106. Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Madsen J, Rutgeerts P, et al. Natalizumab for active Crohn’s disease. N Engl J Med. 2003;348:24–32.

    PubMed  CAS  Google Scholar 

  107. Laberge S, Rabb H, Issekutz TB, Martin JG. Role of VLA-4 and LFA-1 in allergen-induced airway hyperresponsiveness and lung inflammation in the rat. Am J Respir Crit Care Med. 1995;151:822–9.

    PubMed  CAS  Google Scholar 

  108. Offner H, Subramanian S, Parker SM, Wang C, Afentoulis ME, Lewis A, et al. Splenic atrophy in experimental stroke is accompanied by increased regulatory T cells and circulating macrophages. J Immunol. 2006;176:6523–31.

    PubMed  CAS  Google Scholar 

  109. Laffon A, Garcia-Vicuna R, Humbria A, Postigo AA, Corbi AL, de Landazuri MO, et al. Upregulated expression and function of VLA-4 fibronectin receptors on human activated T cells in rheumatoid arthritis. J Clin Invest. 1991;88:546–52.

    PubMed  CAS  Google Scholar 

  110. Podolsky DK. Inflammatory bowel disease (1). N Engl J Med. 1991;325:928–37.

    PubMed  CAS  Google Scholar 

  111. Jackson DY. α4 integrin antagonists. Curr Pharm Des. 2002;8:1229–53.

    PubMed  CAS  Google Scholar 

  112. Yusuf-Makagiansar H, Anderson ME, Yakovleva TV, Murray JS, Siahaan TJ. Inhibition of LFA-1/ICAM-1 and VLA-4/VCAM-1 as a therapeutic approach to inflammation and autoimmune diseases. Med Res Rev. 2002;22:146–67.

    PubMed  CAS  Google Scholar 

  113. Berlin C, Berg EL, Briskin MJ, Andrew DP, Kilshaw PJ, Holzmann B, et al. α4β7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell. 1993;74:185–95.

    PubMed  CAS  Google Scholar 

  114. Hemler ME, Elices MJ, Parker C, Takada Y. Structure of the integrin VLA-4 and its cell-cell and cell-matrix adhesion functions. Immunol Rev. 1990;114:45–65.

    PubMed  CAS  Google Scholar 

  115. Steinman L. Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat Rev Drug Discov. 2005;4:510–8.

    PubMed  CAS  Google Scholar 

  116. Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med. 2005;353:369–74.

    PubMed  CAS  Google Scholar 

  117. Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med. 2005;353:375–81.

    PubMed  CAS  Google Scholar 

  118. Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med. 2005;353:362–8.

    PubMed  Google Scholar 

  119. Koralnik IJ. New insights into progressive multifocal leukoencephalopathy. Curr Opin Neurol. 2004;17:365–70.

    PubMed  Google Scholar 

  120. Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006;354:924–33.

    PubMed  CAS  Google Scholar 

  121. Kummer C, Ginsberg MH. New approaches to blockade of alpha4-integrins, proven therapeutic targets in chronic inflammation. Biochem Pharmacol. 2006;72:1460–8.

    PubMed  CAS  Google Scholar 

  122. Peter K, Schwarz M, Ylanne J, Kohler B, Moser M, Nordt T, et al. Induction of fibrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIb/IIIa (αIIbβ3) inhibitors. Blood. 1998;92:3240–9.

    PubMed  CAS  Google Scholar 

  123. Quinn MJ, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa inhibitors: recognition of a two-edged sword? Circulation. 2002;106:379–85.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This project was supported by NIH HL087088 (M.K.), and NIH HL18208 (M.K.).

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY, 14642, USA

    Young-Min Hyun, Craig T. Lefort & Minsoo Kim

Authors
  1. Young-Min Hyun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Craig T. Lefort
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Minsoo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Minsoo Kim.

Additional information

Young-Min Hyun, and Craig T. Lefort, contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hyun, YM., Lefort, C.T. & Kim, M. Leukocyte integrins and their ligand interactions. Immunol Res 45, 195–208 (2009). https://doi.org/10.1007/s12026-009-8101-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-009-8101-1

Keywords

Search

Navigation