0 13 Costimulation costimulation NN 14 16 of of IN 17 27 peripheral peripheral JJ 28 33 blood blood NN 34 35 T t NN 36 40 cell cell NN 41 51 activation activation NN 52 54 by by IN 55 60 human human JJ 61 72 endothelial endothelial JJ 73 78 cells cell NNS 78 79 . . . 80 88 Enhanced enhance VBN 89 93 IL-2 il-2 NN 94 107 transcription transcription NN 108 118 correlates correlate VBZ 119 123 with with IN 124 133 increased increase VBN 134 139 c-fos c-fos NN 140 149 synthesis synthesis NN 150 153 and and CC 154 163 increased increase VBD 164 167 Fos fos NN 168 175 content content NN 176 178 of of IN 179 183 AP-1 ap-1 NN 183 184 . . . 186 197 Endothelial endothelial JJ 198 203 cells cell NNS 204 205 ( ( ( 205 207 EC EC NNP 207 208 ) ) ) 209 212 act act VBP 213 215 as as IN 216 219 APC APC NNP 220 223 for for IN 224 231 resting rest VBG 232 235 PBL pbl NN 236 238 in in FW 239 244 vitro vitro FW 244 245 , , , 246 249 and and CC 250 253 may may MD 254 258 have have VB 259 268 important important JJ 269 274 roles role NNS 275 277 in in FW 278 282 vivo vivo FW 283 285 in in IN 286 289 the the DT 290 302 pathogenesis pathogenesis NN 303 305 of of IN 306 315 allograft allograft NN 316 325 rejection rejection NN 326 329 and and CC 330 337 delayed delay VBN 338 354 hypersensitivity hypersensitivity NN 354 355 . . . 356 358 We we PRP 359 369 previously previously RB 370 378 reported report VBD 379 383 that that IN 384 389 human human JJ 390 399 umbilical umbilical JJ 400 404 vein vein NN 405 407 EC EC NNP 408 415 provide provide VBP 416 429 costimulatory costimulatory JJ 430 437 signals signal NNS 438 440 to to TO 441 455 PHA-stimulated pha-stimulated JJ 456 459 PBL pbl NN 460 463 via via IN 464 478 CD2:lymphocyte CD2:lymphocyte NNP 479 498 function-associated function-associated JJ 499 503 Ag-3 ag-3 NN 504 507 and and CC 508 510 an an DT 511 523 unidentified unidentified JJ 524 530 ligand ligand NN 531 535 pair pair NN 535 536 , , , 537 546 resulting result VBG 547 549 in in IN 550 551 a a DT 552 558 three- three- CD 559 561 to to TO 562 572 eight-fold eight-fold JJ 573 584 enhancement enhancement NN 585 587 of of IN 588 592 IL-2 il-2 NN 593 603 production production NN 603 604 . . . 605 608 The the DT 609 620 physiologic physiologic JJ 621 630 relevance relevance NN 631 633 of of IN 634 638 this this DT 639 647 increase increase NN 648 651 was be VBD 652 664 demonstrated demonstrate VBN 665 667 by by IN 668 671 the the DT 672 685 proliferative proliferative JJ 686 695 advantage advantage NN 696 704 provided provide VBN 705 707 by by IN 708 710 EC EC NNP 711 713 to to TO 714 717 PBL pbl NN 718 730 suboptimally suboptimally RB 731 741 stimulated stimulate VBN 742 746 with with IN 747 750 mAb mab NN 751 755 OKT3 okt3 NN 755 756 . . . 757 759 We we PRP 760 763 now now RB 764 770 report report VBP 771 775 that that IN 776 778 EC EC NNP 779 792 costimulation costimulation NN 793 799 causes cause VBZ 800 809 increased increase VBN 810 816 levels level NNS 817 819 of of IN 820 824 IL-2 il-2 NN 825 829 mRNA mrna NN 830 832 as as IN 833 834 a a DT 835 841 result result NN 842 844 of of IN 845 854 increased increase VBN 855 859 IL-2 il-2 NN 860 873 transcription transcription NN 874 876 in in IN 877 880 PBL PBL NNP 880 881 . . . 882 884 We we PRP 885 894 therefore therefore RB 895 903 examined examine VBD 904 907 the the DT 908 915 effects effect NNS 916 918 of of IN 919 921 EC EC NNP 922 924 on on IN 925 926 T t NN 927 931 cell cell NN 932 939 nuclear nuclear JJ 940 947 factors factor NNS 948 953 known know VBN 954 956 to to TO 957 965 regulate regulate VB 966 970 IL-2 il-2 NN 971 984 transcription transcription NN 984 985 , , , 986 995 including include VBG 996 1001 c-jun c-jun NN 1002 1005 and and CC 1006 1015 c-fos-two c-fos-two NN 1016 1026 components component NNS 1027 1029 of of IN 1030 1033 the the DT 1034 1047 transcription transcription NN 1048 1054 factor factor NN 1055 1059 AP-1 ap-1 NN 1059 1060 , , , 1061 1065 NFAT NFAT NNP 1065 1066 , , , 1067 1070 and and CC 1071 1077 others other NNS 1077 1078 . . . 1079 1082 PBL PBL NNP 1083 1097 constitutively constitutively RB 1098 1105 express express VBP 1106 1111 c-jun c-jun NN 1112 1123 transcripts transcript NNS 1123 1124 , , , 1125 1128 and and CC 1129 1132 the the DT 1133 1138 level level NN 1139 1141 of of IN 1142 1147 c-jun c-jun NN 1148 1152 mRNA mRNA NNP 1153 1155 is be VBZ 1156 1159 not not RB 1160 1167 altered alter VBN 1168 1170 by by IN 1171 1174 PHA PHA NNP 1175 1185 activation activation NN 1186 1188 in in IN 1189 1192 the the DT 1193 1200 absence absence NN 1201 1203 or or CC 1204 1212 presence presence NN 1213 1215 of of IN 1216 1218 EC EC NNP 1218 1219 . . . 1220 1222 In in IN 1223 1231 contrast contrast NN 1231 1232 , , , 1233 1238 c-fos c-fos NN 1239 1243 mRNA mRNA NNP 1244 1246 is be VBZ 1247 1253 absent absent JJ 1254 1258 from from IN 1259 1266 resting rest VBG 1267 1268 T t NN 1269 1274 cells cell NNS 1275 1278 and and CC 1279 1281 is be VBZ 1282 1289 induced induce VBN 1290 1292 on on IN 1293 1296 PHA PHA NNP 1297 1307 activation activation NN 1307 1308 . . . 1309 1311 EC EC NNP 1312 1317 alone alone RB 1318 1320 do do VBP 1321 1324 not not RB 1325 1331 induce induce VB 1332 1337 c-fos c-fos NN 1338 1342 mRNA mrna NN 1343 1346 but but CC 1347 1354 augment augment VBP 1355 1358 the the DT 1359 1364 level level NN 1365 1367 of of IN 1368 1373 c-fos c-fos NN 1374 1378 mRNA mrna NN 1379 1381 in in IN 1382 1395 PHA-activated pha-activated JJ 1396 1397 T t NN 1398 1403 cells cell NNS 1404 1406 by by IN 1407 1409 3- 3- CD 1410 1412 to to TO 1413 1420 10-fold 10-fold RB 1420 1421 . . . 1422 1426 This this DT 1427 1433 effect effect NN 1434 1436 is be VBZ 1437 1444 largely largely RB 1445 1456 independent independent JJ 1457 1459 of of IN 1460 1463 the the DT 1464 1478 CD2:lymphocyte CD2:lymphocyte NNP 1479 1498 function-associated function-associated JJ 1499 1503 Ag-3 ag-3 NN 1504 1511 pathway pathway NN 1511 1512 . . . 1513 1522 Gel-shift gel-shift JJ 1523 1531 analysis analysis NN 1532 1539 reveals reveal VBZ 1540 1543 the the DT 1544 1556 constitutive constitutive JJ 1557 1565 presence presence NN 1566 1568 of of IN 1569 1576 nuclear nuclear JJ 1577 1584 factors factor NNS 1585 1587 in in IN 1588 1595 resting rest VBG 1596 1599 PBL pbl NN 1600 1604 that that WDT 1605 1609 bind bind VBP 1610 1612 to to TO 1613 1616 the the DT 1617 1625 proximal proximal JJ 1626 1630 AP-1 ap-1 NN 1631 1635 site site NN 1636 1638 of of IN 1639 1642 the the DT 1643 1647 IL-2 il-2 NN 1648 1656 promoter promoter NN 1657 1660 and and CC 1661 1665 that that WDT 1666 1673 contain contain VBP 1674 1688 immunoreactive immunoreactive JJ 1689 1694 c-Jun c-jun NN 1695 1698 but but CC 1699 1702 not not RB 1703 1708 c-Fos c-fos NN 1709 1716 protein protein NN 1716 1717 . . . 1718 1720 In in IN 1721 1729 contrast contrast NN 1729 1730 , , , 1731 1735 AP-1 ap-1 NN 1736 1740 from from IN 1741 1754 PHA-activated pha-activated JJ 1755 1760 cells cell NNS 1761 1769 contains contain VBZ 1770 1775 c-Jun c-jun NN 1776 1779 and and CC 1780 1783 low low JJ 1784 1790 levels level NNS 1791 1793 of of IN 1794 1799 c-Fos c-fos NN 1799 1800 . . . 1801 1811 Strikingly strikingly RB 1811 1812 , , , 1813 1826 costimulation costimulation NN 1827 1831 with with IN 1832 1834 EC EC NNP 1835 1842 results result VBZ 1843 1845 in in IN 1846 1847 a a DT 1848 1856 dramatic dramatic JJ 1857 1865 increase increase NN 1866 1867 ( ( ( 1867 1869 up up RB 1870 1872 to to TO 1873 1880 15-fold 15-fold JJ 1880 1881 ) ) ) 1882 1884 in in IN 1885 1888 the the DT 1889 1894 c-Fos c-fos NN 1895 1902 content content NN 1903 1905 of of IN 1906 1910 AP-1 ap-1 NN 1910 1911 . . . 1912 1918 Levels level NNS 1919 1921 of of IN 1922 1927 other other JJ 1928 1935 nuclear nuclear JJ 1936 1943 factors factor NNS 1944 1952 involved involve VBN 1953 1955 in in IN 1956 1960 IL-2 il-2 NN 1961 1971 regulation regulation NN 1972 1976 were be VBD 1977 1980 not not RB 1981 1988 altered alter VBN 1989 1991 by by IN 1992 1994 EC EC NNP 1994 1995 , , , 1996 2004 although although IN 2005 2013 NFAT-DNA NFAT-DNA NNP 2014 2023 complexes complex NNS 2024 2032 migrated migrate VBD 2033 2035 at at IN 2036 2037 a a DT 2038 2046 slightly slightly RB 2047 2056 different different JJ 2057 2065 mobility mobility NN 2065 2066 . . . 2067 2069 In in IN 2070 2077 summary summary NN 2077 2078 , , , 2079 2082 our our PRP$ 2083 2087 data datum NNS 2088 2095 suggest suggest VBP 2096 2100 that that IN 2101 2108 changes change NNS 2109 2111 in in IN 2112 2115 the the DT 2116 2127 composition composition NN 2128 2130 of of IN 2131 2144 transcription transcription NN 2145 2151 factor factor NN 2152 2156 AP-1 ap-1 NN 2157 2159 is be VBZ 2160 2161 a a DT 2162 2165 key key JJ 2166 2175 molecular molecular JJ 2176 2185 mechanism mechanism NN 2186 2189 for for IN 2190 2200 increasing increase VBG 2201 2205 IL-2 il-2 NN 2206 2219 transcription transcription NN 2220 2223 and and CC 2224 2227 may may MD 2228 2236 underlie underlie VB 2237 2240 the the DT 2241 2251 phenomenon phenomenon NN 2252 2254 of of IN 2255 2268 costimulation costimulation NN 2269 2271 by by IN 2272 2274 EC EC NNP 2274 2275 . . .