0 9 Defective defective JJ 10 23 transcription transcription NN 24 26 of of IN 27 30 the the DT 31 35 IL-2 il-2 NN 36 40 gene gene NN 41 43 is be VBZ 44 54 associated associate VBN 55 59 with with IN 60 68 impaired impaired JJ 69 79 expression expression NN 80 82 of of IN 83 88 c-Fos c-fos NN 88 89 , , , 90 94 FosB FosB NNP 94 95 , , , 96 99 and and CC 100 104 JunB JunB NNP 105 107 in in IN 108 115 anergic anergic JJ 116 117 T t NN 118 124 helper helper NN 125 126 1 1 CD 127 132 cells cell NNS 132 133 . . . 135 142 Anergic anergic JJ 143 147 CD4+ cd4+ JJ 148 150 Th Th NNP 151 156 cells cell NNS 157 159 do do VBP 160 163 not not RB 164 171 produce produce VB 172 176 IL-2 il-2 NN 177 181 when when WRB 182 192 challenged challenge VBN 193 197 with with IN 198 207 Ag-pulsed ag-pulsed JJ 208 217 accessory accessory JJ 218 223 cells cell NNS 224 231 because because IN 232 234 of of IN 235 236 a a DT 237 252 transcriptional transcriptional JJ 253 259 defect defect NN 259 260 . . . 261 263 In in IN 264 268 this this DT 269 273 work work NN 273 274 , , , 275 277 we we PRP 278 284 report report VBP 285 289 that that IN 290 295 these these DT 296 303 anergic anergic JJ 304 305 T t NN 306 311 cells cell NNS 312 315 are be VBP 316 325 defective defective JJ 326 328 in in IN 329 334 their their PRP$ 335 342 ability ability NN 343 345 to to TO 346 357 up-regulate up-regulate VB 358 365 protein protein NN 366 373 binding binding NN 374 377 and and CC 378 393 transactivation transactivation NN 394 396 at at IN 397 400 two two CD 401 409 critical critical JJ 410 414 IL-2 il-2 NN 415 418 DNA dna NN 419 427 enhancer enhancer NN 428 436 elements element NNS 436 437 : : : 438 443 NF-AT NF-AT NNP 444 445 ( ( ( 445 452 nuclear nuclear JJ 453 459 factor factor NN 460 462 of of IN 463 472 activated activate VBN 473 474 T t NN 475 480 cells cell NNS 480 481 ; ; : 482 483 a a DT 484 492 sequence sequence NN 493 497 that that WDT 498 503 binds bind VBZ 504 505 a a DT 506 520 heterotrimeric heterotrimeric JJ 521 526 NFATp NFATp NNP 526 527 , , , 528 531 Fos Fos NNP 531 532 , , , 533 536 and and CC 537 540 Jun Jun NNP 541 548 protein protein NN 549 556 complex complex NN 556 557 ) ) ) 558 561 and and CC 562 571 Activator Activator NNP 572 581 Protein-1 Protein-1 NNP 582 583 ( ( ( 583 587 AP-1 AP-1 NNP 587 588 ) ) ) 589 590 ( ( ( 590 594 that that WDT 595 600 binds bind VBZ 601 604 Fos Fos NNP 605 608 and and CC 609 612 Jun Jun NNP 613 625 heterodimers heterodimer NNS 625 626 ) ) ) 626 627 . . . 628 635 Western western NN 636 640 blot blot NN 641 649 analysis analysis NN 650 652 of of IN 653 660 nuclear nuclear JJ 661 669 extracts extract NNS 670 676 showed show VBD 677 681 that that IN 682 685 the the DT 686 694 impaired impaired JJ 695 706 DNA-protein dna-protein JJ 707 719 interactions interaction NNS 720 722 in in IN 723 730 anergic anergic JJ 731 732 T t NN 733 738 cells cell NNS 739 743 were be VBD 744 754 associated associate VBN 755 759 with with IN 760 764 poor poor JJ 765 775 expression expression NN 776 778 of of IN 779 782 the the DT 783 792 inducible inducible JJ 793 797 AP-1 ap-1 NN 798 804 family family NN 805 812 members member NNS 813 818 c-Fos c-fos NN 818 819 , , , 820 824 FosB FosB NNP 824 825 , , , 826 829 and and CC 830 834 JunB JunB NNP 834 835 . . . 836 843 However however RB 843 844 , , , 845 848 the the DT 849 856 reduced reduce VBN 857 867 expression expression NN 868 870 of of IN 871 876 these these DT 877 885 proteins protein NNS 886 889 was be VBD 890 893 not not RB 894 897 the the DT 898 904 result result NN 905 907 of of IN 908 909 a a DT 910 916 global global JJ 917 934 TCR/CD3-signaling tcr/cd3-signaling JJ 935 941 defect defect NN 942 949 because because IN 950 953 CD3 CD3 NNP 954 967 cross-linking cross-linking NN 968 975 induced induce VBD 976 978 an an DT 979 989 equivalent equivalent JJ 990 998 increase increase NN 999 1001 in in IN 1002 1020 intracellular-free intracellular-free JJ 1021 1028 calcium calcium NN 1029 1033 ions ion NNS 1033 1034 , , , 1035 1037 as as RB 1038 1042 well well RB 1043 1045 as as IN 1046 1051 NFATp NFATp NNP 1052 1069 dephosphorylation dephosphorylation NN 1069 1070 , , , 1071 1084 translocation translocation NN 1085 1087 to to TO 1088 1091 the the DT 1092 1099 nucleus nucleus NN 1099 1100 , , , 1101 1104 and and CC 1105 1108 DNA DNA NNP 1109 1116 binding binding NN 1117 1119 in in IN 1120 1124 both both CC 1125 1131 normal normal JJ 1132 1135 and and CC 1136 1143 anergic anergic JJ 1144 1145 T t NN 1146 1151 cells cell NNS 1151 1152 . . . 1153 1157 Thus thus RB 1157 1158 , , , 1159 1168 defective defective JJ 1169 1173 IL-2 il-2 NN 1174 1178 gene gene NN 1179 1192 transcription transcription NN 1193 1200 appears appear VBZ 1201 1203 to to TO 1204 1206 be be VB 1207 1210 due due JJ 1210 1211 , , , 1212 1214 at at IN 1215 1220 least least JJS 1221 1223 in in IN 1224 1228 part part NN 1228 1229 , , , 1230 1232 to to TO 1233 1234 a a DT 1235 1244 selective selective JJ 1245 1250 block block NN 1251 1253 in in IN 1254 1257 the the DT 1258 1268 expression expression NN 1269 1271 of of IN 1272 1275 the the DT 1276 1280 AP-1 AP-1 NNP 1281 1284 Fos Fos NNP 1285 1288 and and CC 1289 1292 Jun Jun NNP 1293 1299 family family NN 1300 1307 members member NNS 1308 1310 in in IN 1311 1318 anergic anergic JJ 1319 1320 T t NN 1321 1326 cells cell NNS 1326 1327 . . .