0 5 Alpha Alpha NNP 6 7 4 4 CD 8 12 beta beta NN 13 14 1 1 CD 15 16 ( ( ( 16 26 CD49d/CD29 cd49d/cd29 NN 26 27 ) ) ) 28 36 integrin integrin NN 37 50 costimulation costimulation NN 51 53 of of IN 54 59 human human JJ 60 61 T t NN 62 67 cells cell NNS 68 76 enhances enhance VBZ 77 90 transcription transcription NN 91 97 factor factor NN 98 101 and and CC 102 110 cytokine cytokine NN 111 120 induction induction NN 121 123 in in IN 124 127 the the DT 128 135 absence absence NN 136 138 of of IN 139 146 altered altered JJ 147 158 sensitivity sensitivity NN 159 161 to to TO 162 170 anti-CD3 anti-cd3 JJ 171 182 stimulation stimulation NN 182 183 . . . 185 188 The the DT 189 197 integrin integrin NN 198 203 alpha alpha NN 204 205 4 4 CD 206 210 beta beta NN 211 212 1 1 CD 213 216 can can MD 217 224 provide provide VB 225 226 a a DT 227 237 costimulus costimulus NN 238 240 to to TO 241 247 induce induce VB 248 252 IL-2 il-2 NN 253 262 secretion secretion NN 263 266 and and CC 267 272 IL-2R il-2r NN 273 283 expression expression NN 284 291 leading lead VBG 292 294 to to TO 295 303 enhanced enhance VBN 304 317 proliferation proliferation NN 318 320 of of IN 321 329 purified purify VBN 329 330 , , , 331 341 peripheral peripheral JJ 342 347 blood blood NN 348 349 T t NN 350 355 cells cell NNS 355 356 . . . 357 364 Similar similar JJ 365 367 to to TO 368 378 expression expression NN 379 381 of of IN 382 386 IL-2 il-2 NN 386 387 , , , 388 390 we we PRP 391 403 demonstrated demonstrate VBD 404 408 that that IN 409 420 recombinant recombinant JJ 421 434 vascular-cell vascular-cell JJ 435 443 adhesion adhesion NN 444 454 molecule-1 molecule-1 NN 454 455 , , , 456 460 when when WRB 461 475 co-immobilized co-immobilize VBN 476 480 with with IN 481 489 anti-CD3 anti-cd3 JJ 490 493 mAb mab NN 493 494 , , , 495 508 significantly significantly RB 509 517 enhanced enhance VBD 518 521 the the DT 522 531 induction induction NN 532 534 of of IN 535 548 transcription transcription NN 549 556 factors factor NNS 557 562 NF-AT NF-AT NNP 562 563 , , , 564 568 AP-1 ap-1 NN 568 569 , , , 570 573 and and CC 574 582 NF-kappa NF-kappa NNP 583 584 B B NNP 585 587 as as IN 588 598 determined determine VBN 599 601 by by IN 602 617 electromobility electromobility NN 618 623 shift shift NN 624 631 assays. assays. NN 632 637 alpha alpha NN 638 639 4 4 CD 640 644 beta beta NN 645 646 1 1 CD 647 655 ligation ligation NN 656 661 alone alone RB 662 665 had have VBD 666 668 no no DT 669 675 effect effect NN 676 678 on on IN 679 692 transcription transcription NN 693 699 factor factor NN 700 707 binding binding NN 707 708 . . . 709 712 The the DT 713 725 requirements requirement NNS 726 729 for for IN 730 739 induction induction NN 740 742 of of IN 743 756 transcription transcription NN 757 764 factors factor NNS 765 774 reflected reflect VBD 775 778 the the DT 779 791 requirements requirement NNS 792 795 for for IN 796 799 the the DT 800 809 secretion secretion NN 810 812 of of IN 813 821 multiple multiple JJ 822 831 cytokines cytokine NNS 831 832 , , , 833 842 including include VBG 843 847 IL-2 il-2 NN 847 848 , , , 849 858 TNF-alpha TNF-alpha NNP 858 859 , , , 860 869 IFN-gamma IFN-gamma NNP 869 870 , , , 871 874 and and CC 875 886 granulocyte granulocyte NN 887 901 macrophage-CSF macrophage-csf NN 901 902 . . . 903 905 In in IN 906 914 contrast contrast NN 915 917 to to TO 918 925 freshly freshly RB 926 934 isolated isolate VBN 935 936 T t NN 937 942 cells cell NNS 942 943 , , , 944 946 in in IN 947 961 vitro-cultured vitro-cultured JJ 962 963 T t NN 964 969 cells cell NNS 970 973 did do VBD 974 977 not not RB 978 985 require require VB 986 999 costimulation costimulation NN 1000 1003 for for IN 1004 1012 cytokine cytokine NN 1013 1022 secretion secretion NN 1023 1025 in in IN 1026 1034 response response NN 1035 1037 to to TO 1038 1046 anti-CD3 anti-cd3 NN 1047 1052 alone alone RB 1052 1053 . . . 1054 1064 Comparison comparison NN 1065 1067 of of IN 1068 1071 the the DT 1072 1076 dose dose NN 1077 1085 response response NN 1086 1088 to to TO 1089 1097 anti-CD3 anti-cd3 JJ 1098 1109 stimulation stimulation NN 1110 1122 demonstrated demonstrate VBD 1123 1127 that that IN 1128 1140 half-maximal half-maximal JJ 1141 1150 induction induction NN 1151 1153 of of IN 1154 1158 IL-2 il-2 NN 1159 1162 was be VBD 1163 1171 achieved achieve VBN 1172 1177 using use VBG 1178 1181 the the DT 1182 1186 same same JJ 1187 1191 dose dose NN 1192 1194 of of IN 1195 1203 anti-CD3 anti-cd3 NN 1204 1207 for for IN 1208 1212 both both DT 1213 1220 freshly freshly RB 1221 1229 isolated isolate VBN 1230 1233 and and CC 1234 1242 cultured culture VBN 1243 1244 T t NN 1245 1250 cells cell NNS 1250 1251 . . . 1252 1263 Furthermore furthermore RB 1263 1264 , , , 1265 1268 the the DT 1269 1273 dose dose NN 1274 1276 of of IN 1277 1281 OKT3 OKT3 NNP 1282 1290 required require VBN 1291 1293 to to TO 1294 1301 achieve achieve VB 1302 1314 half-maximal half-maximal JJ 1315 1325 activation activation NN 1326 1329 was be VBD 1330 1333 the the DT 1334 1338 same same JJ 1339 1344 using use VBG 1345 1348 PMA PMA NNP 1349 1351 or or CC 1352 1361 different different JJ 1362 1376 concentrations concentration NNS 1377 1379 of of IN 1380 1385 alpha alpha NN 1386 1387 4 4 CD 1388 1392 beta beta NN 1393 1394 1 1 CD 1395 1402 ligands ligand NNS 1402 1403 . . . 1404 1413 Therefore therefore RB 1413 1414 , , , 1415 1428 costimulation costimulation NN 1429 1431 by by IN 1432 1437 alpha alpha NN 1438 1439 4 4 CD 1440 1444 beta beta NN 1445 1446 1 1 CD 1447 1454 ligands ligand NNS 1455 1458 was be VBD 1459 1462 not not RB 1463 1466 due due JJ 1467 1469 to to TO 1470 1483 stabilization stabilization NN 1484 1486 of of IN 1487 1490 the the DT 1491 1502 interaction interaction NN 1503 1505 of of IN 1506 1509 the the DT 1510 1515 cells cell NNS 1516 1520 with with IN 1521 1524 its its PRP$ 1525 1534 substrate substrate NN 1534 1535 . . . 1536 1538 We we PRP 1539 1547 conclude conclude VBP 1547 1548 , , , 1549 1555 rather rather RB 1555 1556 , , , 1557 1561 that that IN 1562 1567 alpha alpha NN 1568 1569 4 4 CD 1570 1574 beta beta NN 1575 1576 1 1 CD 1577 1579 in in IN 1580 1587 freshly freshly RB 1588 1596 isolated isolate VBN 1597 1598 T t NN 1599 1604 cells cell NNS 1605 1613 delivers deliver VBZ 1614 1615 a a DT 1616 1624 distinct distinct JJ 1625 1631 signal signal NN 1632 1636 that that WDT 1637 1647 synergizes synergize VBZ 1648 1653 early early RB 1654 1658 with with IN 1659 1666 signals signal NNS 1667 1676 initiated initiate VBN 1677 1679 by by IN 1680 1687 TCR/CD3 tcr/cd3 NN 1688 1696 ligation ligation NN 1697 1699 to to TO 1700 1706 induce induce VB 1707 1710 DNA dna NN 1711 1718 binding binding NN 1719 1721 of of IN 1722 1730 multiple multiple JJ 1731 1744 transcription transcription NN 1745 1752 factors factor NNS 1753 1761 required require VBN 1762 1765 for for IN 1766 1774 cytokine cytokine NN 1775 1779 gene gene NN 1780 1789 induction induction NN 1789 1790 . . .