0 13 Rel-deficient rel-deficient JJ 14 15 T t NN 16 21 cells cell NNS 22 29 exhibit exhibit VBP 30 37 defects defect NNS 38 40 in in IN 41 51 production production NN 52 54 of of IN 55 66 interleukin interleukin NN 67 68 3 3 CD 69 72 and and CC 73 95 granulocyte-macrophage granulocyte-macrophage JJ 96 114 colony-stimulating colony-stimulating JJ 115 121 factor factor NN 121 122 . . . 124 127 The the DT 128 133 c-rel c-rel NN 134 147 protooncogene protooncogene NN 148 155 encodes encode VBZ 156 157 a a DT 158 165 subunit subunit NN 166 168 of of IN 169 172 the the DT 173 181 NF-kappa NF-kappa NNP 182 188 B-like b-like JJ 189 195 family family NN 196 198 of of IN 199 212 transcription transcription NN 213 220 factors factor NNS 220 221 . . . 222 226 Mice mouse NNS 227 234 lacking lack VBG 235 238 Rel Rel NNP 239 242 are be VBP 243 252 defective defective JJ 253 255 in in IN 256 265 mitogenic mitogenic JJ 266 276 activation activation NN 277 279 of of IN 280 281 B B NNP 282 285 and and CC 286 287 T t NN 288 299 lymphocytes lymphocyte NNS 300 303 and and CC 304 311 display display VBP 312 320 impaired impaired JJ 321 328 humoral humoral JJ 329 337 immunity immunity NN 337 338 . . . 339 341 In in IN 342 344 an an DT 345 352 attempt attempt NN 353 355 to to TO 356 364 identify identify VB 365 372 changes change NNS 373 375 in in IN 376 380 gene gene NN 381 391 expression expression NN 392 396 that that WDT 397 406 accompany accompany VBP 407 410 the the DT 411 417 T-cell t-cell NN 418 429 stimulation stimulation NN 430 437 defects defect NNS 438 448 associated associate VBN 449 453 with with IN 454 457 the the DT 458 462 loss loss NN 463 465 of of IN 466 469 Rel Rel NNP 469 470 , , , 471 473 we we PRP 474 478 have have VBP 479 487 examined examine VBN 488 491 the the DT 492 502 expression expression NN 503 505 of of IN 506 510 cell cell NN 511 518 surface surface NN 519 529 activation activation NN 530 537 markers marker NNS 538 541 and and CC 542 550 cytokine cytokine NN 551 561 production production NN 562 564 in in IN 565 583 mitogen-stimulated mitogen-stimulated JJ 584 590 Rel-/- rel-/- JJ 591 592 T t NN 593 598 cells cell NNS 598 599 . . . 600 603 The the DT 604 614 expression expression NN 615 617 of of IN 618 622 cell cell NN 623 630 surface surface NN 631 638 markers marker NNS 639 648 including include VBG 649 652 the the DT 653 664 interleukin interleukin NN 665 666 2 2 CD 667 675 receptor receptor NN 676 681 alpha alpha NN 682 683 ( ( ( 683 688 IL-2R IL-2R NNP 689 694 alpha alpha NN 694 695 ) ) ) 696 701 chain chain NN 702 703 ( ( ( 703 707 CD25 cd25 NN 707 708 ) ) ) 708 709 , , , 710 714 CD69 CD69 NNP 715 718 and and CC 719 729 L-selectin L-selectin NNP 730 731 ( ( ( 731 735 CD62 cd62 NN 735 736 ) ) ) 737 739 is be VBZ 740 746 normal normal JJ 747 749 in in IN 750 767 mitogen-activated mitogen-activated JJ 768 774 Rel-/- rel-/- JJ 775 776 T t NN 777 782 cells cell NNS 782 783 , , , 784 787 but but CC 788 796 cytokine cytokine NN 797 807 production production NN 808 810 is be VBZ 811 819 impaired impaired JJ 819 820 . . . 821 823 In in IN 824 830 Rel-/- rel-/- JJ 831 838 splenic splenic JJ 839 840 T t NN 841 845 cell cell NN 846 854 cultures culture NNS 855 865 stimulated stimulate VBN 866 870 with with IN 871 878 phorbol phorbol NN 879 891 12-myristate 12-myristate NN 892 902 13-acetate 13-acetate NN 903 906 and and CC 907 916 ionomycin ionomycin NN 916 917 , , , 918 921 the the DT 922 928 levels level NNS 929 931 of of IN 932 936 IL-3 IL-3 NNP 936 937 , , , 938 942 IL-5 IL-5 NNP 942 943 , , , 944 956 granulocyte- granulocyte- NN 957 967 macrophage macrophage NN 968 986 colony-stimulating colony-stimulating JJ 987 993 factor factor NN 994 995 ( ( ( 995 1001 GM-CSF GM-CSF NNP 1001 1002 ) ) ) 1002 1003 , , , 1004 1009 tumor tumor NN 1010 1018 necrosis necrosis NN 1019 1025 factor factor NN 1026 1031 alpha alpha NN 1032 1033 ( ( ( 1033 1042 TNF-alpha TNF-alpha NNP 1042 1043 ) ) ) 1043 1044 , , , 1045 1048 and and CC 1049 1054 gamma gamma NN 1055 1065 interferon interferon NN 1066 1067 ( ( ( 1067 1076 IFN-gamma IFN-gamma NNP 1076 1077 ) ) ) 1078 1082 were be VBD 1083 1087 only only RB 1088 1090 2- 2- CD 1091 1093 to to TO 1094 1100 3-fold 3-fold RB 1101 1106 lower low JJR 1107 1115 compared compare VBN 1116 1120 with with IN 1121 1127 normal normal JJ 1128 1129 T t NN 1130 1135 cells cell NNS 1135 1136 . . . 1137 1139 In in IN 1140 1148 contrast contrast NN 1148 1149 , , , 1150 1158 anti-CD3 anti-cd3 JJ 1159 1162 and and CC 1163 1172 anti-CD28 anti-cd28 JJ 1173 1183 stimulated stimulate VBN 1184 1190 Rel-/- rel-/- JJ 1191 1192 T t NN 1193 1198 cells cell NNS 1198 1199 , , , 1200 1205 which which WDT 1206 1210 fail fail VBP 1211 1213 to to TO 1214 1225 proliferate proliferate VB 1225 1226 , , , 1227 1231 make make VB 1232 1238 little little JJ 1239 1241 or or CC 1242 1244 no no DT 1245 1255 detectable detectable JJ 1256 1265 cytokines cytokine NNS 1265 1266 . . . 1267 1276 Exogenous exogenous JJ 1277 1281 IL-2 IL-2 NNP 1281 1282 , , , 1283 1288 which which WDT 1289 1299 restitutes restitute VBZ 1300 1303 the the DT 1304 1317 proliferative proliferative JJ 1318 1326 response response NN 1327 1329 of of IN 1330 1333 the the DT 1334 1343 anti-CD3- anti-cd3- JJ 1344 1347 and and CC 1348 1365 anti-CD28-treated anti-cd28-treated JJ 1366 1372 Rel-/- rel-/- JJ 1373 1374 T t NN 1375 1380 cells cell NNS 1380 1381 , , , 1382 1390 restores restore VBZ 1391 1401 production production NN 1402 1404 of of IN 1405 1409 IL-5 IL-5 NNP 1409 1410 , , , 1411 1420 TNF-alpha TNF-alpha NNP 1420 1421 , , , 1422 1425 and and CC 1426 1435 IFN-gamma IFN-gamma NNP 1435 1436 , , , 1437 1440 but but CC 1441 1444 not not RB 1445 1449 IL-3 IL-3 NNP 1450 1453 and and CC 1454 1460 GM-CSF GM-CSF NNP 1461 1471 expression expression NN 1472 1474 to to TO 1475 1488 approximately approximately RB 1489 1495 normal normal JJ 1496 1502 levels level NNS 1502 1503 . . . 1504 1506 In in IN 1507 1515 contrast contrast NN 1516 1518 to to TO 1519 1536 mitogen-activated mitogen-activated JJ 1537 1543 Rel-/- rel-/- JJ 1544 1545 T t NN 1546 1551 cells cell NNS 1551 1552 , , , 1553 1582 lipopolysaccharide-stimulated lipopolysaccharide-stimulated JJ 1583 1589 Rel-/- rel-/- JJ 1590 1601 macrophages macrophage NNS 1602 1609 produce produce VBP 1610 1616 higher high JJR 1617 1621 than than IN 1622 1628 normal normal JJ 1629 1635 levels level NNS 1636 1638 of of IN 1639 1645 GM-CSF GM-CSF NNP 1645 1646 . . . 1647 1652 These these DT 1653 1661 findings finding NNS 1662 1671 establish establish VBP 1672 1676 that that IN 1677 1680 Rel Rel NNP 1681 1684 can can MD 1685 1693 function function VB 1694 1696 as as IN 1697 1699 an an DT 1700 1709 activator activator NN 1710 1712 or or CC 1713 1722 repressor repressor NN 1723 1725 of of IN 1726 1730 gene gene NN 1731 1741 expression expression NN 1742 1745 and and CC 1746 1748 is be VBZ 1749 1757 required require VBN 1758 1760 by by IN 1761 1762 T t NN 1763 1774 lymphocytes lymphocyte NNS 1775 1778 for for IN 1779 1789 production production NN 1790 1792 of of IN 1793 1797 IL-3 IL-3 NNP 1798 1801 and and CC 1802 1808 GM-CSF GM-CSF NNP 1808 1809 . . .