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• W2140305004 abstract "Intercellular adhesion molecule 3 (ICAM-3; CD50) is the predominant counter-receptor on resting T cells and monocytes for the leukocyte integrin, lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18), and may play an important role in the initial stages of the T cell-dependent immune response. Deletion of individual immunoglobulin superfamily (IgSF) domains of ICAM-3 and ICAM-3 IgSF domain chimeras with CD21 showed there is a single LFA-1 binding site in ICAM-3 and that IgSF domain 1 is necessary and sufficient for LFA-1 binding. Epitope mapping and functional studies performed with 17 anti-ICAM-3 monoclonal antibodies demonstrated that only some monoclonal antibodies, with epitopes wholly within domain 1 of ICAM-3, were able to block binding of ICAM-3 bearing cells to purified LFA-1, in agreement with the data obtained from the domain deletion mutants and CD21 chimeras. Analysis of a panel of 45 point mutants of domain 1 of ICAM-3 identified five residues that may contact LFA-1 as part of the binding site, Asn23, Ser25, Glu37, Phe54, and Gln75. These five residues are predicted by molecular modeling, based on the structure of vascular cell adhesion molecule 1 (VCAM-1), to cluster in two distinct locations on domain 1 of ICAM-3 on the BED face (Asn23 and Ser25) and on the C strand or CD loop (E37), the E strand (F54), and the FG loop (Q75). The residues, Asn23 and Ser25, comprise a consensus N-linked glycosylation site. Intercellular adhesion molecule 3 (ICAM-3; CD50) is the predominant counter-receptor on resting T cells and monocytes for the leukocyte integrin, lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18), and may play an important role in the initial stages of the T cell-dependent immune response. Deletion of individual immunoglobulin superfamily (IgSF) domains of ICAM-3 and ICAM-3 IgSF domain chimeras with CD21 showed there is a single LFA-1 binding site in ICAM-3 and that IgSF domain 1 is necessary and sufficient for LFA-1 binding. Epitope mapping and functional studies performed with 17 anti-ICAM-3 monoclonal antibodies demonstrated that only some monoclonal antibodies, with epitopes wholly within domain 1 of ICAM-3, were able to block binding of ICAM-3 bearing cells to purified LFA-1, in agreement with the data obtained from the domain deletion mutants and CD21 chimeras. Analysis of a panel of 45 point mutants of domain 1 of ICAM-3 identified five residues that may contact LFA-1 as part of the binding site, Asn23, Ser25, Glu37, Phe54, and Gln75. These five residues are predicted by molecular modeling, based on the structure of vascular cell adhesion molecule 1 (VCAM-1), to cluster in two distinct locations on domain 1 of ICAM-3 on the BED face (Asn23 and Ser25) and on the C strand or CD loop (E37), the E strand (F54), and the FG loop (Q75). The residues, Asn23 and Ser25, comprise a consensus N-linked glycosylation site. INTRODUCTIONIntercellular adhesion molecule 3 (ICAM-3, CD50) 1The abbreviations used are: ICAMintercellular adhesion moleculemAbmonoclonal antibody(ies)IgSFimmunoglobulin superfamilyLFA-1lymphocyte function-associated antigen 1VCAMvascular cell adhesion moleculeCAMcell adhesion moleculeBCECF2′,7′-bis-(2-carboxyethyl)-5-(and −6)-carboxyfluorescein, acetoxymethyl ester. is a 120-kDa single chain glycoprotein found exclusively on leukocytes (1de Fougerolles A.R. Springer T.A. J. Exp. Med. 1992; 175: 185-190Google Scholar, 2Cordell J.L. Pulford K. Turley H. Jones M. Micklem K. Doussis I.A. Tyler X. Mayne K. Gatter K.C. Mason D.Y. J. Clin. Pathol. 1994; 47: 143-147Google Scholar) and most highly expressed on T cells, where it is the predominant LFA-1 counter-receptor (3de Fougerolles A.R. Qin X. Springer T.A. J. Exp. Med. 1994; 179: 619-629Google Scholar, 4Campanero M.R. delPozo M.A. Arroyo A.G. Sanchez-Mateos P. Hernandez T. Craig A. Pulido R. Sanchez-Madrid F. J. Cell. Biol. 1993; 123: 1007-1016Google Scholar). The existence of ICAM-3 was inferred by the observation that anti-LFA-1 monoclonal antibodies (mAb) completely inhibited the PMA-stimulated homotypic aggregation of a T cell line, whereas a combination of blocking anti-ICAM-1 and anti-ICAM-2 mAb only partially inhibited aggregation (5de Fougerolles A.R. Stacker S.A. Schwarting R. Springer T.A. J. Exp. Med. 1991; 174: 253-267Google Scholar). ICAM-3 was subsequently characterized with the mAb, IC3/1 (1de Fougerolles A.R. Springer T.A. J. Exp. Med. 1992; 175: 185-190Google Scholar), and it was later determined that the previously anonymous leukocyte antigen, CD50, is identical to ICAM-3 (6Juan M. Vilella R. Mila J. Yagüe J. Miralles A. Campbell K.S. Friedrich R.J. Cambier J. Vives J. de Fougerolles A.R. Springer T.A. Eur. J. Immunol. 1993; 23: 1508-1512Google Scholar). ICAM-3 is constitutively expressed on leukocytes in contrast to the inducibly expressed ICAM-1 and is not present on endothelium or platelets as is ICAM-2 (7Klickstein L.B. Springer T.A. Schlossman S.F. Boumsell L. Gilks W. Harlan J. Kishimoto T. Morimoto T. Ritz J. Shaw S. Silverstein R. Springer T. Tedder T. Todd R. Leucocyte typing V: White Cell Differentiation Antigens. Oxford University Press, New York1995: 1546Google Scholar). Functional activities of anti-ICAM-3 mAb include partial blocking of the allogeneic mixed lymphocyte reaction (2Cordell J.L. Pulford K. Turley H. Jones M. Micklem K. Doussis I.A. Tyler X. Mayne K. Gatter K.C. Mason D.Y. J. Clin. Pathol. 1994; 47: 143-147Google Scholar, 8Vilella R. Mila J. Lozano F. Alberola-ila J. Places L. Vives J. Tissue Antigens. 1990; 36: 203-210Google Scholar) and co-stimulatory activity for resting T cells (2Cordell J.L. Pulford K. Turley H. Jones M. Micklem K. Doussis I.A. Tyler X. Mayne K. Gatter K.C. Mason D.Y. J. Clin. Pathol. 1994; 47: 143-147Google Scholar, 9Hernandez-Caselles T. Rubio G. Campanero M.R. del Pozo M.A. Muro M. Sanchez-Madrid F. Aparicio P. Eur. J. Immunol. 1993; 23: 2799-2806Google Scholar, 10Starling G.C. Egner W. McLellan A.D. Daish A. Cordell J. Mason D.Y. Simmons D.L. Hart D.N.J. Schlossman S.F. Boumsell L. Gilks W. Harlan J. Kishimoto T. Morimoto T. Ritz J. Shaw S. Silverstein R. Springer T. Tedder T. Todd R. Leukocyte Typing V: White Cell Differentiation Antigens. Oxford University Press, New York1995: 1578Google Scholar).ICAM-3 recently was cloned independently by three groups (11Fawcett J. Holness C.L.L. Needham L.A. Turley H. Gatter K.C. Mason D.Y. Simmons D.L. Nature. 1992; 360: 481-484Google Scholar, 12Vazeux R. Hoffman P.A. Tomita J.K. Dickinson E.S. Jasman R.L. John T.St. Gallatin W.M. Nature. 1992; 360: 485-488Google Scholar, 13de Fougerolles A.R. Klickstein L.B. Springer T.A. J. Exp. Med. 1993; 177: 1187-1192Google Scholar), which revealed a type 1 integral membrane protein with a 37-amino acid cytoplasmic region containing 5 serine and 2 tyrosine residues in contrast to ICAM-1 and ICAM-2, which have no serine and only 1 tyrosine in the cytoplasmic domain (14Staunton D.E. Marlin S.D. Stratowa C. Dustin M.L. Springer T.A. Cell. 1988; 52: 925-933Google Scholar, 15Simmons D. Makgoba M.W. Seed B. Nature. 1988; 331: 624-627Google Scholar, 16Staunton D.E. Dustin M.L. Springer T.A. Nature. 1989; 339: 61-64Google Scholar). ICAM-3 contains a 25-residue transmembrane region and a 456-residue mature extracellular domain comprising five immunoglobulin superfamily (IgSF) domains. ICAM-3 is 52% identical to ICAM-1 and 37% identical to ICAM-2 in the corresponding regions.In previous studies of ICAM-1, domain transfer and deletion mutagenesis revealed that the LFA-1 binding site was located within the amino-terminal two IgSF domains (17Staunton D.E. Dustin M.L. Erickson H.P. Springer T.A. Cell. 1990; 61: 243-254Google Scholar, 18Berendt A.R. McDowall A. Craig A.G. Bates P.A. Sternberg M.J.E. Marsh K. Newbold C.I. Hogg K. Cell. 1992; 68: 71-81Google Scholar). Expression of IgSF domain 1 or domain 2 of ICAM-1 in the absence of one another has not been achieved, and point mutations that disrupt conformation suggest that these two domains are conformationally interdependent. Point mutations were identified within domains 1 and 2 that affected binding of transfected cells to purified LFA-1, although the E34A and Q73H mutations within domain 1 had the greatest effect (17Staunton D.E. Dustin M.L. Erickson H.P. Springer T.A. Cell. 1990; 61: 243-254Google Scholar). The epitopes of mAb that blocked ICAM-1-dependent binding to purified LFA-1 were mapped within domain 1 (e.g. RR1/1) or domain 2 (e.g. R6.5) (17Staunton D.E. Dustin M.L. Erickson H.P. Springer T.A. Cell. 1990; 61: 243-254Google Scholar). Studies with synthetic peptides of ICAM-2 found that a 22-mer oligopeptide derived from the sequence of domain 1 of ICAM-2, residues Gly21 through Ser42 inclusive, could inhibit by 50% the binding of endothelial cells to purified LFA-1 at a concentration of 15 μM (19Li R. Nortamo P. Valmu L. Tolvanen M. Huuskonen J. Kantor C. Gahmberg C.G. J. Biol. Chem. 1993; 268: 17513-17518Google Scholar). Peptides shortened from either end were significantly less active. The corresponding peptide based on the ICAM-1 sequence was 10-fold less active. Others have reported inhibitory function for peptides derived from the second domain of ICAM-2 (20Seth R. Salcedo R. Patarroyo M. Makgoba M.W. FEBS Lett. 1991; 282: 193-196Google Scholar), the second domain of ICAM-1 (21Ross L. Hassman F. Molony L. J. Biol. Chem. 1992; 267: 8537-8543Google Scholar), and the fourth domain of ICAM-1 (22Fecondo J.V. Kent S.B.H. Boyd A.W. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 2879-2882Google Scholar). Domain deletion, point mutagenesis, and epitope mapping studies of vascular cell adhesion molecule 1 (VCAM-1) (23Vonderheide R.H. Tedder T.F. Springer T.A. Staunton D.E. J. Cell Biol. 1994; 125: 215-222Google Scholar, 24Osborn L. Vassallo C. Browning B.G. Tizard R. Haskard D.O. Benjamin C.D. Douglas I. Kirchhausen T. J. Cell Biol. 1994; 124(4): 601-608Google Scholar), an IgSF member that binds to the β-1 integrin VLA-4, found two distinct homologous binding sites, in IgSF domains 1 and 4, and the existence of a 5-residue motif important for the binding of CAMs to integrins in both of these domains was proposed (23Vonderheide R.H. Tedder T.F. Springer T.A. Staunton D.E. J. Cell Biol. 1994; 125: 215-222Google Scholar, 24Osborn L. Vassallo C. Browning B.G. Tizard R. Haskard D.O. Benjamin C.D. Douglas I. Kirchhausen T. J. Cell Biol. 1994; 124(4): 601-608Google Scholar).In this study of ICAM-3, in contrast to what has been reported for ICAM-1, we demonstrate that IgSF domain 1 of ICAM-3 is sufficient for functional expression of the LFA-1 binding site. Furthermore, in contrast to what has been reported for VCAM-1 and ICAM-2, ICAM-3 does not contain a linear sequence centered around Glu37 (corresponding to residue Glu34 of ICAM-1, residue Asp40 of VCAM-1, and residue Glu40 of ICAM-2) that is necessary for binding to LFA-1, although Glu37 itself is essential. Mutation of five noncontiguous residues within domain 1 of ICAM-3 disrupts binding to LFA-1 without affecting mAb epitopes in domain 1. These residues are predicted to localize at two distinct regions on the three-dimensional model of IgSF domain 1 of ICAM-3.RESULTSOligonucleotide-directed mutagenesis was used to create a panel of four IgSF domain deletions (Fig. 1). All four deletion mutants directed the expression in transfected COS cells of antigenic ICAM-3 at comparable levels (Table I). COS cell transfectants were assayed for binding to purified LFA-1 on plastic (Fig. 1). The construct, ΔD1, in which domain 1 was deleted, did not direct binding of transfected COS cells to purified LFA-1. In contrast, the constructions lacking domains 2, 3, or 4 directed binding to purified LFA-1 at near wild type levels (Fig. 1). All ICAM-3-mediated binding was inhibitable by pretreating the coated plates with an LFA-1-specific mAb, confirming the specificity of the assay.Table IMonoclonal antibody epitope localization by immunofluorescent flow cytometry of COS cell transfectants analyzedmAb nameVector controlICAM-3ΔD1ΔD2ΔD3ΔD4CBR-IC2/233 (7Klickstein L.B. Springer T.A. Schlossman S.F. Boumsell L. Gilks W. Harlan J. Kishimoto T. Morimoto T. Ritz J. Shaw S. Silverstein R. Springer T. Tedder T. Todd R. Leucocyte typing V: White Cell Differentiation Antigens. Oxford University Press, New York1995: 1546Google Scholar)35 (9Hernandez-Caselles T. Rubio G. Campanero M.R. del Pozo M.A. Muro M. Sanchez-Madrid F. Aparicio P. Eur. J. Immunol. 1993; 23: 2799-2806Google Scholar)32 (7Klickstein L.B. Springer T.A. Schlossman S.F. Boumsell L. Gilks W. Harlan J. Kishimoto T. Morimoto T. Ritz J. Shaw S. Silverstein R. Springer T. Tedder T. Todd R. Leucocyte typing V: White Cell Differentiation Antigens. Oxford University Press, New York1995: 1546Google Scholar)31 (6Juan M. Vilella R. Mila J. Yagüe J. Miralles A. Campbell K.S. Friedrich R.J. Cambier J. Vives J. de Fougerolles A.R. Springer T.A. Eur. J. Immunol. 1993; 23: 1508-1512Google Scholar)33 (7Klickstein L.B. Springer T.A. Schlossman S.F. Boumsell L. Gilks W. Harlan J. Kishimoto T. Morimoto T. Ritz J. Shaw S. Silverstein R. Springer T. Tedder T. Todd R. Leucocyte typing V: White Cell Differentiation Antigens. Oxford University Press, New York1995: 1546Google Scholar)33 (7Klickstein L.B. Springer T.A. Schlossman S.F. Boumsell L. Gilks W. Harlan J. Kishimoto T. Morimoto T. Ritz J. Shaw S. Silverstein R. Springer T. Tedder T. Todd R. Leucocyte typing V: White Cell Differentiation Antigens. Oxford University Press, New York1995: 1546Google Scholar)BRIC7936 (9Hernandez-Caselles T. Rubio G. Campanero M.R. del Pozo M.A. Muro M. Sanchez-Madrid F. Aparicio P. Eur. J. Immunol. 1993; 23: 2799-2806Google Scholar)445 (67)29(5de Fougerolles A.R. Stacker S.A. Schwarting R. Springer T.A. J. Exp. Med. 1991; 174: 253-267Google Scholar199 (46)196 (47)155 (44)CG10640 (12Vazeux R. Hoffman P.A. Tomita J.K. Dickinson E.S. Jasman R.L. John T.St. Gallatin W.M. Nature. 1992; 360: 485-488Google Scholar)288 (60)33(6Juan M. Vilella R. Mila J. Yagüe J. Miralles A. Campbell K.S. Friedrich R.J. Cambier J. Vives J. de Fougerolles A.R. Springer T.A. Eur. J. Immunol. 1993; 23: 1508-1512Google Scholar)178 (43Klickstein L.B. de Fougerolles A.R. York M.R. Springer T.A. Tissue Antigens. 1993; 42: 270Google Scholar)163 (44)161 (49)WDS 3A943 (15Simmons D. Makgoba M.W. Seed B. Nature. 1988; 331: 624-627Google Scholar)354 (64)45(10Starling G.C. Egner W. McLellan A.D. Daish A. Cordell J. Mason D.Y. Simmons D.L. Hart D.N.J. Schlossman S.F. Boumsell L. Gilks W. Harlan J. Kishimoto T. Morimoto T. Ritz J. Shaw S. Silverstein R. Springer T. Tedder T. Todd R. Leukocyte Typing V: White Cell Differentiation Antigens. Oxford University Press, New York1995: 1578Google Scholar)171 (43Klickstein L.B. de Fougerolles A.R. York M.R. Springer T.A. Tissue Antigens. 1993; 42: 270Google Scholar)168 (46)155 (47)ICO-6042 (14Staunton D.E. Marlin S.D. Stratowa C. Dustin M.L. Springer T.A. Cell. 1988; 52: 925-933Google Scholar)361 (64)36(10Starling G.C. Egner W. McLellan A.D. Daish A. Cordell J. Mason D.Y. Simmons D.L. Hart D.N.J. Schlossman S.F. Boumsell L. Gilks W. Harlan J. Kishimoto T. Morimoto T. Ritz J. Shaw S. Silverstein R. Springer T. Tedder T. Todd R. Leukocyte Typing V: White Cell Differentiation Antigens. Oxford University Press, New York1995: 1578Google Scholar)169 (43Klickstein L.B. de Fougerolles A.R. York M.R. Springer T.A. Tissue Antigens. 1993; 42: 270Google Scholar)158 (45)173 (48)CBR-IC3/134 (7Klickstein L.B. Springer T.A. Schlossman S.F. Boumsell L. Gilks W. Harlan J. Kishimoto T. Morimoto T. Ritz J. Shaw S. Silverstein R. Springer T. Tedder T. Todd R. Leucocyte typing V: White Cell Differentiation Antigens. Oxford University Press, New York1995: 1546Google Scholar)227 (56)31(5de Fougerolles A.R. Stacker S.A. Schwarting R. Springer T.A. J. Exp. Med. 1991; 174: 253-267Google Scholar)106 (35Garrett T.P. Wang J. Yan Y. Liu J. Harrison S.C. J. Mol. Biol. 1993; 234: 763-778Google Scholar)106 (38Landis R.C. McDowall A. Holness C.L.L. Littler A.J. Simmons D.L. Hogg N. J. Cell Biol. 1994; 126: 529-537Google Scholar)129 (41Sadhu C. Lipsky B. Erickson H.P. Hayflick J. Dick K.O. Gallatin W.M. Staunton D.E. Cell Adhes. Commun. 1994; 2: 429-440Google Scholar)CBR-IC3/637 (10Starling G.C. Egner W. McLellan A.D. Daish A. Cordell J. Mason D.Y. Simmons D.L. Hart D.N.J. Schlossman S.F. Boumsell L. Gilks W. Harlan J. Kishimoto T. Morimoto T. Ritz J. Shaw S. Silverstein R. Springer T. Tedder T. Todd R. Leukocyte Typing V: White Cell Differentiation Antigens. Oxford University Press, New York1995: 1578Google Scholar)156 (56)32(6Juan M. Vilella R. Mila J. Yagüe J. Miralles A. Campbell K.S. Friedrich R.J. Cambier J. Vives J. de Fougerolles A.R. Springer T.A. Eur. J. Immunol. 1993; 23: 1508-1512Google Scholar)69 (30Dustin M.L. Springer T.A. Nature. 1989; 341: 619-624Google Scholar)71 (31Diamond M.S. Staunton D.E. de Fougerolles A.R. Stacker S.A. Garcia-Aguilar J. Hibbs M.L. Springer T.A. J. Cell Biol. 1990; 111: 3129-3139Google Scholar)79 (33Jones E.Y. Harlos K. Bottomley M.J. Robinson R.C. Driscoll P.C. Edwards R.M. Clements J.M. Dudgeon T.J. Stuart D.I. Nature. 1995; 373: 539-544Google Scholar)BY4437 (12Vazeux R. Hoffman P.A. Tomita J.K. Dickinson E.S. Jasman R.L. John T.St. Gallatin W.M. Nature. 1992; 360: 485-488Google Scholar)285 (59)33(7Klickstein L.B. Springer T.A. Schlossman S.F. Boumsell L. Gilks W. Harlan J. Kishimoto T. Morimoto T. Ritz J. Shaw S. Silverstein R. Springer T. Tedder T. Todd R. Leucocyte typing V: White Cell Differentiation Antigens. 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Gallatin W.M. Staunton D.E. Cell Adhes. Commun. 1994; 2: 429-440Google Scholar)160 (45)137 (45)CBR-IC3/234 (7Klickstein L.B. Springer T.A. Schlossman S.F. Boumsell L. Gilks W. Harlan J. Kishimoto T. Morimoto T. Ritz J. Shaw S. Silverstein R. Springer T. Tedder T. Todd R. Leucocyte typing V: White Cell Differentiation Antigens. Oxford University Press, New York1995: 1546Google Scholar)378 (63)227 (55)32(7Klickstein L.B. Springer T.A. Schlossman S.F. Boumsell L. Gilks W. Harlan J. Kishimoto T. Morimoto T. Ritz J. Shaw S. Silverstein R. Springer T. Tedder T. Todd R. Leucocyte typing V: White Cell Differentiation Antigens. Oxford University Press, New York1995: 1546Google Scholar)142 (42Holness C.L. Bates P.A. Littler A.J. Buckley C.D. McDowall A. Bossy D. Hogg N. Simmons D.L. J. Biol. Chem. 1995; 270: 877-884Google Scholar)159 (45)TP1/2438 (12Vazeux R. Hoffman P.A. Tomita J.K. Dickinson E.S. Jasman R.L. John T.St. Gallatin W.M. 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Schlossman S.F. Boumsell L. Gilks W. Harlan J. Kishimoto T. Morimoto T. Ritz J. Shaw S. Silverstein R. Springer T. Tedder T. Todd R. Leucocyte typing V: White Cell Differentiation Antigens. Oxford University Press, New York1995: 1546Google Scholar)112 (37Wang J.-H. Pepinsky R.B. Stehle T. Liu J.-H. Karpusas M. Browning B. Osborn L. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5714-5718Google Scholar)165 (47)152-2D1136 (9Hernandez-Caselles T. Rubio G. Campanero M.R. del Pozo M.A. Muro M. Sanchez-Madrid F. Aparicio P. Eur. J. Immunol. 1993; 23: 2799-2806Google Scholar)366 (63)31( 6Juan M. Vilella R. Mila J. Yagüe J. Miralles A. Campbell K.S. Friedrich R.J. Cambier J. Vives J. de Fougerolles A.R. Springer T.A. Eur. J. Immunol. 1993; 23: 1508-1512Google Scholar)33(6Juan M. Vilella R. Mila J. Yagüe J. Miralles A. Campbell K.S. Friedrich R.J. Cambier J. Vives J. de Fougerolles A.R. Springer T.A. Eur. J. Immunol. 1993; 23: 1508-1512Google Scholar)137 (41Sadhu C. Lipsky B. Erickson H.P. 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Nucleic Acids Res. 1984; 12: 387-395Google Scholar)62 (29Selden R.F. Howie K.B. Rowe M.E. Goodman H.M. Moore D.D. Mol. Cell. Biol. 1986; 6: 3173-3179Google Scholar)32(5de Fougerolles A.R. Stacker S.A. Schwarting R. Springer T.A. J. Exp. Med. 1991; 174: 253-267Google Scholar)CBR-IC3/535 (8Vilella R. Mila J. Lozano F. Alberola-ila J. Places L. Vives J. Tissue Antigens. 1990; 36: 203-210Google Scholar)215 (57)156 (50)95 (37Wang J.-H. Pepinsky R.B. Stehle T. Liu J.-H. Karpusas M. Browning B. Osborn L. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5714-5718Google Scholar)83 (35Garrett T.P. Wang J. Yan Y. Liu J. Harrison S.C. J. Mol. Biol. 1993; 234: 763-778Google Scholar)31(6Juan M. Vilella R. Mila J. Yagüe J. Miralles A. Campbell K.S. Friedrich R.J. Cambier J. Vives J. de Fougerolles A.R. Springer T.A. Eur. J. Immunol. 1993; 23: 1508-1512Google Scholar) Open table in a new tab The above results demonstrated that domain 1 of ICAM-3 is required for binding to LFA-1 but did not rule out a contribution from the other IgSF domains. To determine whether domain 1 of ICAM-3 was able to mediate specific binding to purified LFA-1 out of the context of adjacent IgSF domains, sequences encoding domain 1 of ICAM-3, domains 1 and 2, or domains 1, 2, and 3 were transferred to the sequence encoding the amino-terminal end of short consensus repeat 3 of CD21 (Fig. 2). The short consensus repeat sequences comprising the entire extracellular region of CD21 have no homology with IgSF members and are independent structural units (27Lowell C.A. Klickstein L.B. Carter R.H. Mitchell J.A. Fearon D.T. Ahearn J.M. J. Exp. Med. 1989; 170: 1931-1946Google Scholar). COS cells transiently expressing the chimeric proteins displayed the CD21 epitope for the HB-5 mAb and the expected ICAM-3 mAb epitopes (data not shown). COS cells expressing wild type ICAM-3 but not COS cells transfected with the AprM9 vector alone or with a cDNA encoding the full-length CD21 bound to purified LFA-1 (Fig. 2). COS cells expressing the CD21 chimeras containing domain 1 of ICAM-3, domains 1 and 2, and domains 1, 2, and 3 bound to LFA-1 at 50-78% of wild type levels (Fig. 2). The lower binding of the chimeras with respect to wild type ICAM-3 is likely accounted for by the lower expression levels of the chimeras on COS cells observed in all five experiments (not shown). These results demonstrate that an LFA-1 binding site is wholly contained within domain 1 of ICAM-3.Fig. 2Binding of COS cells expressing ICAM-3-CD21 chimeras to purified LFA-1 on plastic. The structures of the chimeras and the parent molecules are shown in the upper panel. The large ovals represent IgSF domains, and the smaller, shaded ovals represent the short consensus repeats (SCRs) comprising the CD21 extracellular domain. The lower panel shows the results of a representative LFA-1 binding assay of COS cells transiently expressing the indicated cDNAs, as described in the legend to Fig. 1.View Large Image Figure ViewerDownload (PPT)The ICAM-3 domain deletion mutants were transiently expressed in COS cells and examined for the presence of the epitopes defined by 17 ICAM-3 mAb clustered in the 5th Leukocyte Typing Workshop (7Klickstein L.B. Springer T.A. Schlossman S.F. Boumsell L. Gilks W. Harlan J. Kishimoto T. Morimoto T. Ritz J. Shaw S. Silverstein R. Springer T. Tedder T. Todd R. Leucocyte typing V: White Cell Differentiation Antigens. Oxford University Press, New York1995: 1546Google Scholar) by indirect immunofluorescence and flow cytometry. Four mAb groups were identified (Table I). Nine mAb failed to bind to cells expressing the mutant lacking domain 1 but bound well to cells expressing all the other domain deletions, suggesting that the epitope(s) for these mAb are within domain 1 of ICAM-3 (Table I). Three mAb failed to bind to cells expressing the mutant lacking domain 2 but bound well to cells expressing all the other domain deletions, suggesting that the epitope(s) for these mAb are within domain 2 of ICAM-3 (Table I). Two mAb required the presence of both domains 1 and 2 for expression of their epitopes. Three mAb required the presence of domain 4 but not domains 1, 2, or 3 for epitope expression (Table I). Similar results were obtained with stably transfected L cells (data not shown).The 17 anti-ICAM-3 mAb were assayed in the presence of mAb to ICAM-1 and ICAM-2 for the ability to inhibit binding of fluorescently labeled Jurkat T cells to purified LFA-1 adsorbed to plastic. Four mAb with epitopes that mapped to domain 1 of ICAM-3 completely blocked binding of Jurkat cells to purified LFA-1 (Fig. 3). The five other mAb to domain 1 of ICAM-3 inhibited by approximately 50% the binding of Jurkat cells to purified LFA-1, and all other mAb did not significantly inhibit binding (Fig. 3). These data confirm that domain 1 of ICAM-3 is necessary for binding to LFA-1 and support the finding that the other ICAM-3 domains do not contribute to the binding site. Furthermore, unlike ICAM-1 (17Staunton D.E. Dustin M.L. Erickson H.P. Springer T.A. Cell. 1990; 61: 243-254Google Scholar, 18Berendt A.R. McDowall A. Craig A.G. Bates P.A. Sternberg M.J.E. Marsh K. Newbold C.I. Hogg K. Cell. 1992; 68: 71-81Google Scholar), domain 1 of ICAM-3 may be expressed independently of domain 2.Fig. 3Effect of anti-ICAM-3 monoclonal antibodies on binding of Jurkat cells to purified LFA-1 on plastic. Jurkat cells labeled with the fluorescent dye BCECF were preincubated with RR1/1 + IC2/2 mAb to block ICAM-1 and ICAM-2, respectively, and with the indicated anti-ICAM-3 antibody and then added to the wells of a 96-well plate coated with purified LFA-1. The percentage of binding was determined by analysis with a fluorescence concentration analyzer before and after washing. X63 is a nonbinding negative control myeloma, and TS1/22 is a blocking anti-LFA-1 antibody used as a positive control. Antibodies were used at 10 μg/ml or at a 1:100 dilution of ascites. The error bars indicate the standard deviation of the average of six experiments, except that BRIC79 was studied in three experiments.View Large Image Figure ViewerDownload (PPT)The sequence of domain 1 of ICAM-3 was aligned with the sequence of domains of other IgSF members that bind integrins: domain 1 of ICAM-2, ICAM-3, mucosal addressin CAM-1, and VCAM-1 and domain 4 of VCAM-1. All residues conserved among the CAMs, except for the four invariant cysteines, and residues conserved among ICAMs but not among VCAMs or mucosal addressin CAM were subjected to site-directed mutagenesis. Additionally, residues previously suggested to be important in interactions with integrins and all five potential N-linked glycosylation sites were changed (Fig. 4). In general, residues were substituted with alanine, except alanine and valine were substituted with serine. Mutants were named with the one-letter code, with a slash separating the wild type and mutated residues. A “Δ” indicates deletion of the residues that follow, and the suffix “rev” refers to a wild type revertant of the indicated mutation. All mutant cDNAs were expressed at comparable levels and directed the expression of ICAM-3 with an intact domain" @default.
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