0 1 A a DT 2 17 CD28-associated cd28-associated JJ 18 27 signaling signaling NN 28 35 pathway pathway NN 36 43 leading lead VBG 44 46 to to TO 47 55 cytokine cytokine NN 56 60 gene gene NN 61 74 transcription transcription NN 75 78 and and CC 79 80 T t NN 81 85 cell cell NN 86 99 proliferation proliferation NN 100 107 without without IN 108 111 TCR TCR NNP 112 122 engagement engagement NN 122 123 . . . 125 136 Stimulation stimulation NN 137 139 of of IN 140 147 resting rest VBG 148 153 human human JJ 154 155 T t NN 156 161 cells cell NNS 162 166 with with IN 167 170 the the DT 171 184 CD28-specific cd28-specific JJ 185 188 mAb mab NN 189 191 BW BW NNP 192 195 828 828 CD 196 203 induces induce VBZ 204 217 proliferation proliferation NN 218 221 and and CC 222 230 cytokine cytokine NN 231 240 synthesis synthesis NN 241 248 without without IN 249 256 further further JJ 257 268 requirement requirement NN 269 272 for for IN 273 276 TCR TCR NNP 277 289 coengagement coengagement NN 289 290 . . . 291 295 This this DT 296 307 observation observation NN 308 316 prompted prompt VBD 317 319 us us PRP 320 322 to to TO 323 332 postulate postulate VB 333 337 that that IN 338 344 signal signal NN 345 346 2 2 CD 347 348 ( ( ( 348 361 costimulatory costimulatory JJ 362 368 signal signal NN 368 369 ) ) ) 370 375 alone alone RB 376 383 without without IN 384 390 signal signal NN 391 392 1 1 CD 393 394 ( ( ( 394 397 TCR TCR NNP 398 404 signal signal NN 404 405 ) ) ) 406 409 can can MD 410 418 activate activate VB 419 420 T t NN 421 426 cells cell NNS 426 427 . . . 428 430 To to TO 431 435 test test VB 436 443 whether whether IN 444 448 this this DT 449 457 putative putative JJ 458 466 function function NN 467 469 of of IN 470 474 CD28 cd28 NN 475 477 is be VBZ 478 486 mediated mediate VBN 487 490 via via IN 491 492 a a DT 493 503 particular particular JJ 504 513 signaling signaling NN 514 521 pathway pathway NN 521 522 , , , 523 525 we we PRP 526 534 compared compare VBD 535 540 early early JJ 541 550 signaling signaling NN 551 557 events event NNS 558 567 initiated initiate VBN 568 570 in in IN 571 578 resting rest VBG 579 580 T t NN 581 586 cells cell NNS 587 589 by by IN 590 593 the the DT 594 605 stimulatory stimulatory JJ 606 609 mAb mab NN 610 612 BW BW NNP 613 616 828 828 CD 617 621 with with IN 622 629 signals signal NNS 630 639 triggered trigger VBN 640 642 by by IN 643 646 the the DT 647 661 nonstimulating nonstimulating JJ 662 666 CD28 cd28 NN 667 670 mAb mab NN 671 674 9.3 9.3 CD 674 675 . . . 676 687 Stimulation stimulation NN 688 690 of of IN 691 692 T t NN 693 698 cells cell NNS 699 703 with with IN 704 706 BW BW NNP 707 710 828 828 CD 711 718 induced induce VBD 719 721 an an DT 722 730 increase increase NN 731 733 in in IN 734 747 intracellular intracellular JJ 748 752 Ca2+ ca2+ NN 752 753 , , , 754 757 but but CC 758 761 did do VBD 762 765 not not RB 766 770 lead lead VB 771 773 to to TO 774 784 detectable detectable JJ 785 795 activation activation NN 796 798 of of IN 799 802 the the DT 803 810 protein protein NN 811 818 kinases kinase NNS 819 827 p56(lck) p56(lck) NN 828 831 and and CC 832 839 c-Raf-1 c-raf-1 NN 839 840 . . . 841 845 This this DT 846 853 pathway pathway NN 854 862 resulted result VBD 863 865 in in IN 866 869 the the DT 870 879 induction induction NN 880 882 of of IN 883 886 the the DT 887 900 transcription transcription NN 901 908 factors factor NNS 909 917 NF-kappa NF-kappa NNP 918 919 B B NNP 919 920 , , , 921 926 NF-AT NF-AT NNP 926 927 , , , 928 931 and and CC 932 940 proteins protein NNS 941 948 binding bind VBG 949 951 to to TO 952 955 the the DT 956 960 CD28 cd28 NN 961 969 response response NN 970 977 element element NN 978 980 of of IN 981 984 the the DT 985 989 IL-2 il-2 NN 990 998 promoter promoter NN 998 999 . . . 1000 1002 On on IN 1003 1006 the the DT 1007 1012 other other JJ 1013 1017 hand hand NN 1017 1018 , , , 1019 1030 stimulation stimulation NN 1031 1033 of of IN 1034 1035 T t NN 1036 1041 cells cell NNS 1042 1046 with with IN 1047 1050 mAb mab NN 1051 1054 9.3 9.3 CD 1055 1064 increased increase VBD 1065 1068 the the DT 1069 1074 level level NN 1075 1077 of of IN 1078 1091 intracellular intracellular JJ 1092 1096 Ca2+ ca2+ NN 1097 1100 and and CC 1101 1110 triggered trigger VBD 1111 1114 the the DT 1115 1125 activation activation NN 1126 1128 of of IN 1129 1137 p56(lck) p56(lck) NN 1138 1141 and and CC 1142 1149 c-Raf-1 c-raf-1 NN 1149 1150 , , , 1151 1154 but but CC 1155 1158 was be VBD 1159 1165 unable unable JJ 1166 1168 to to TO 1169 1175 induce induce VB 1176 1179 the the DT 1180 1187 binding binding NN 1188 1190 of of IN 1191 1204 transcription transcription NN 1205 1212 factors factor NNS 1213 1215 to to TO 1216 1219 the the DT 1220 1224 IL-2 il-2 NN 1225 1233 promoter promoter NN 1233 1234 . . . 1235 1237 In in IN 1238 1246 contrast contrast NN 1247 1249 to to TO 1250 1253 the the DT 1254 1266 differential differential JJ 1267 1276 signaling signaling NN 1277 1279 of of IN 1280 1282 BW BW NNP 1283 1286 828 828 CD 1287 1290 and and CC 1291 1294 9.3 9.3 CD 1295 1297 in in IN 1298 1305 resting rest VBG 1306 1307 T t NN 1308 1313 cells cell NNS 1313 1314 , , , 1315 1318 the the DT 1319 1322 two two CD 1323 1327 mAbs mab NNS 1328 1337 exhibited exhibit VBD 1338 1339 a a DT 1340 1347 similar similar JJ 1348 1355 pattern pattern NN 1356 1358 of of IN 1359 1364 early early JJ 1365 1374 signaling signaling NN 1375 1381 events event NNS 1382 1384 in in IN 1385 1394 activated activate VBN 1395 1396 T t NN 1397 1402 cells cell NNS 1403 1406 and and CC 1407 1413 Jurkat jurkat NN 1414 1419 cells cell NNS 1420 1421 ( ( ( 1421 1429 p56(lck) p56(lck) NN 1430 1440 activation activation NN 1440 1441 , , , 1442 1453 association association NN 1454 1456 of of IN 1457 1477 phosphatidylinositol phosphatidylinositol NN 1478 1486 3-kinase 3-kinase NNP 1487 1491 with with IN 1492 1496 CD28 CD28 NNP 1496 1497 ) ) ) 1497 1498 , , , 1499 1509 indicating indicate VBG 1510 1514 that that IN 1515 1518 the the DT 1519 1528 signaling signaling NN 1529 1537 capacity capacity NN 1538 1540 of of IN 1541 1545 CD28 cd28 NN 1546 1553 changes change NNS 1554 1558 with with IN 1559 1569 activation activation NN 1569 1570 . . . 1571 1576 These these DT 1577 1581 data datum NNS 1582 1589 support support VBP 1590 1593 the the DT 1594 1598 view view NN 1599 1603 that that IN 1604 1615 stimulation stimulation NN 1616 1623 through through IN 1624 1628 CD28 cd28 NN 1629 1632 can can MD 1633 1639 induce induce VB 1640 1644 some some DT 1645 1653 effector effector NN 1654 1663 functions function NNS 1664 1666 in in IN 1667 1668 T t NN 1669 1674 cells cell NNS 1675 1678 and and CC 1679 1686 suggest suggest VBP 1687 1691 that that IN 1692 1696 this this DT 1697 1705 capacity capacity NN 1706 1708 is be VBZ 1709 1719 associated associate VBN 1720 1724 with with IN 1725 1726 a a DT 1727 1737 particular particular JJ 1738 1745 pattern pattern NN 1746 1748 of of IN 1749 1754 early early JJ 1755 1764 signaling signaling NN 1765 1771 events event NNS 1771 1772 . . .