0 7 Altered alter VBN 8 14 memory memory NN 15 16 T t NN 17 21 cell cell NN 22 37 differentiation differentiation NN 38 40 in in IN 41 49 patients patient NNS 50 54 with with IN 55 60 early early JJ 61 71 rheumatoid rheumatoid JJ 72 81 arthritis arthritis NN 81 82 . . . 84 87 The the DT 88 95 chronic chronic JJ 96 102 immune immune JJ 103 111 response response NN 112 114 in in IN 115 125 rheumatoid rheumatoid JJ 126 135 arthritis arthritis NN 136 137 ( ( ( 137 139 RA RA NNP 139 140 ) ) ) 141 146 might might MD 147 149 be be VB 150 156 driven drive VBN 157 159 by by IN 160 169 activated activate VBN 170 173 Th1 th1 NN 174 179 cells cell NNS 180 187 without without IN 188 198 sufficient sufficient JJ 199 202 Th2 th2 NN 203 207 cell cell NN 208 223 differentiation differentiation NN 224 226 to to TO 227 240 down-modulate down-modulate VB 241 253 inflammation inflammation NN 253 254 . . . 255 257 To to TO 258 262 test test VB 263 270 whether whether IN 271 281 disordered disorder VBN 282 288 memory memory NN 289 290 T t NN 291 295 cell cell NN 296 311 differentiation differentiation NN 312 323 contributes contribute VBZ 324 326 to to TO 327 330 the the DT 331 338 typical typical JJ 339 352 Th1-dominated th1-dominated JJ 353 360 chronic chronic JJ 361 373 inflammation inflammation NN 374 376 in in IN 377 379 RA RA NNP 380 382 we we PRP 383 395 investigated investigate VBD 396 411 differentiation differentiation NN 412 414 of of IN 415 422 resting rest VBG 423 427 CD4+ cd4+ JJ 428 434 memory memory NN 435 436 T t NN 437 442 cells cell NNS 443 445 in in IN 446 454 patients patient NNS 455 459 with with IN 460 465 early early JJ 466 467 ( ( ( 467 468 6 6 CD 469 471 wk wk NN 472 474 to to TO 475 477 12 12 CD 478 480 mo mo NN 480 481 ) ) ) 482 491 untreated untreated JJ 492 494 RA RA NNP 495 498 and and CC 499 501 in in IN 502 506 age- age- NN 507 510 and and CC 511 522 sex-matched sex-matched JJ 523 530 healthy healthy JJ 531 539 controls control NNS 540 542 in in FW 543 548 vitro vitro FW 548 549 . . . 550 552 No no DT 553 563 difference difference NN 564 566 in in IN 567 575 cytokine cytokine NN 576 585 secretion secretion NN 586 594 profiles profile NNS 595 597 of of IN 598 605 freshly freshly RB 606 614 isolated isolate VBN 615 621 memory memory NN 622 623 T t NN 624 629 cells cell NNS 630 633 was be VBD 634 642 detected detect VBN 643 650 between between IN 651 659 patients patient NNS 660 663 and and CC 664 672 controls control NNS 672 673 . . . 674 675 A a DT 676 680 cell cell NN 681 688 culture culture NN 689 695 system system NN 696 699 was be VBD 700 704 then then RB 705 713 employed employ VBN 714 718 that that WDT 719 728 permitted permit VBD 729 732 the the DT 733 748 differentiation differentiation NN 749 751 of of IN 752 754 Th th NN 755 764 effectors effector NNS 765 769 from from IN 770 777 resting rest VBG 778 784 memory memory NN 785 786 T t NN 787 792 cells cell NNS 793 795 by by IN 796 801 short short JJ 802 806 term term NN 807 814 priming priming NN 814 815 . . . 816 822 Marked marked JJ 823 834 differences difference NNS 835 839 were be VBD 840 845 found find VBN 846 848 in in IN 849 857 response response NN 858 860 to to TO 861 868 priming priming NN 868 869 . . . 870 873 Th2 th2 NN 874 879 cells cell NNS 880 885 could could MD 886 888 be be VB 889 896 induced induce VBN 897 899 in in IN 900 903 all all DT 904 911 healthy healthy JJ 912 920 controls control NNS 921 923 by by IN 924 931 priming prim VBG 932 936 with with IN 937 946 anti-CD28 anti-cd28 NN 947 949 in in IN 950 953 the the DT 954 961 absence absence NN 962 964 of of IN 965 968 TCR TCR NNP 969 977 ligation ligation NN 977 978 . . . 979 981 By by IN 982 990 contrast contrast NN 990 991 , , , 992 999 priming prim VBG 1000 1005 under under IN 1006 1011 those those DT 1012 1022 conditions condition NNS 1023 1031 resulted result VBD 1032 1034 in in IN 1035 1038 Th2 th2 NN 1039 1054 differentiation differentiation NN 1055 1057 in in IN 1058 1062 only only RB 1063 1064 9 9 CD 1065 1067 of of IN 1068 1070 24 24 CD 1071 1073 RA RA NNP 1074 1082 patients patient NNS 1082 1083 . . . 1084 1093 Exogenous exogenous JJ 1094 1098 IL-4 il-4 NN 1099 1104 could could MD 1105 1113 overcome overcome VB 1114 1117 the the DT 1118 1126 apparent apparent JJ 1127 1130 Th2 th2 NN 1131 1146 differentiation differentiation NN 1147 1153 defect defect NN 1154 1156 in in IN 1157 1162 seven seven CD 1163 1171 patients patient NNS 1172 1175 but but CC 1176 1179 was be VBD 1180 1187 without without IN 1188 1194 effect effect NN 1195 1197 in in IN 1198 1201 the the DT 1202 1211 remaining remain VBG 1212 1217 eight eight CD 1218 1226 patients patient NNS 1226 1227 . . . 1228 1230 In in IN 1231 1234 all all DT 1235 1243 patients patient NNS 1244 1245 a a DT 1246 1252 marked marked JJ 1253 1261 decrease decrease NN 1262 1264 in in IN 1265 1279 IL-2-producing il-2-producing JJ 1280 1285 cells cell NNS 1286 1289 and and CC 1290 1291 a a DT 1292 1303 significant significant JJ 1304 1312 increase increase NN 1313 1315 in in IN 1316 1335 well-differentiated well-differentiated JJ 1336 1339 Th1 th1 NN 1340 1345 cells cell NNS 1346 1350 that that WDT 1351 1359 produced produce VBD 1360 1369 IFN-gamma IFN-gamma NNP 1370 1373 but but CC 1374 1377 not not RB 1378 1382 IL-2 il-2 NN 1383 1387 were be VBD 1388 1395 evident evident JJ 1396 1401 after after IN 1402 1409 priming prim VBG 1410 1414 with with IN 1415 1423 anti-CD3 anti-cd3 NN 1424 1427 and and CC 1428 1437 anti-CD28 anti-cd28 NN 1437 1438 . . . 1439 1442 The the DT 1443 1447 data datum NNS 1448 1455 suggest suggest VBP 1456 1460 that that IN 1461 1465 CD4+ cd4+ JJ 1466 1472 memory memory NN 1473 1474 T t NN 1475 1480 cells cell NNS 1481 1485 from from IN 1486 1494 patients patient NNS 1495 1499 with with IN 1500 1505 early early JJ 1506 1515 untreated untreated JJ 1516 1518 RA RA NNP 1519 1527 manifest manifest VBP 1528 1530 an an DT 1531 1540 intrinsic intrinsic JJ 1541 1552 abnormality abnormality NN 1553 1555 in in IN 1556 1561 their their PRP$ 1562 1569 ability ability NN 1570 1572 to to TO 1573 1586 differentiate differentiate VB 1587 1591 into into IN 1592 1600 specific specific JJ 1601 1619 cytokine-producing cytokine-producing JJ 1620 1628 effector effector NN 1629 1634 cells cell NNS 1635 1639 that that WDT 1640 1645 might might MD 1646 1656 contribute contribute VB 1657 1659 to to TO 1660 1663 the the DT 1664 1678 characteristic characteristic JJ 1679 1692 Th1-dominated th1-dominated JJ 1693 1700 chronic chronic JJ 1701 1702 ( ( ( 1702 1713 auto)immune auto)immune JJ 1714 1726 inflammation inflammation NN 1727 1729 in in IN 1730 1732 RA RA NNP 1732 1733 . . .