0 1 A a DT 2 10 negative negative JJ 11 15 role role NN 16 19 for for IN 20 36 phosphoinositide phosphoinositide NN 37 45 3-kinase 3-kinase NNP 46 48 in in IN 49 55 T-cell t-cell NN 56 63 antigen antigen NN 64 72 receptor receptor NN 73 81 function function NN 81 82 . . . 84 94 BACKGROUND background NN 94 95 : : : 96 97 A a DT 98 106 delicate delicate JJ 107 114 balance balance NN 115 122 between between IN 123 131 positive positive JJ 132 135 and and CC 136 144 negative negative JJ 145 155 regulatory regulatory JJ 156 166 mechanisms mechanism NNS 167 173 during during IN 174 180 T-cell t-cell NN 181 191 activation activation NN 192 202 determines determine VBZ 203 206 the the DT 207 218 specificity specificity NN 219 222 and and CC 223 232 magnitude magnitude NN 233 235 of of IN 236 238 an an DT 239 245 immune immune JJ 246 254 response response NN 254 255 . . . 256 272 Phosphoinositide Phosphoinositide NNP 273 281 3-kinase 3-kinase NNP 282 283 ( ( ( 283 285 PI PI NNP 286 294 3-kinase 3-kinase NNP 294 295 ) ) ) 296 298 is be VBZ 299 308 activated activate VBN 309 311 by by IN 312 313 a a DT 314 321 diverse diverse JJ 322 325 set set NN 326 328 of of IN 329 338 receptors receptor NNS 339 343 that that WDT 344 353 determine determine VBP 354 360 T-cell t-cell NN 361 369 function function NN 369 370 , , , 371 380 including include VBG 381 384 the the DT 385 391 T-cell t-cell NN 392 399 antigen antigen NN 400 408 receptor receptor NN 409 410 ( ( ( 410 413 TCR TCR NNP 413 414 ) ) ) 414 415 , , , 416 419 the the DT 420 433 costimulatory costimulatory JJ 434 442 receptor receptor NN 443 447 CD28 cd28 NN 447 448 , , , 449 452 and and CC 453 461 negative negative JJ 462 472 regulators regulator NNS 473 475 of of IN 476 482 T-cell t-cell NN 483 493 activation activation NN 494 498 such such JJ 499 501 as as IN 502 508 CTLA-4 ctla-4 NN 508 509 . . . 510 512 PI pi NN 513 521 3-kinase 3-kinase NNP 522 524 is be VBZ 525 529 also also RB 530 539 regulated regulate VBN 540 542 by by IN 543 546 the the DT 547 561 haematopoietic haematopoietic JJ 562 571 cytokines cytokine NNS 572 576 that that WDT 577 586 determine determine VBP 587 593 T-cell t-cell NN 594 609 differentiation differentiation NN 610 613 and and CC 614 624 lymphocyte lymphocyte NN 625 638 proliferation proliferation NN 638 639 . . . 640 642 PI pi NN 643 651 3-kinase 3-kinase NNP 652 655 can can MD 656 660 thus thus RB 661 672 dynamically dynamically RB 673 682 influence influence VB 683 686 the the DT 687 694 outcome outcome NN 695 697 of of IN 698 701 the the DT 702 708 immune immune JJ 709 718 reactions reaction NNS 719 721 at at IN 722 729 various various JJ 730 736 stages stage NNS 736 737 . . . 738 740 In in IN 741 745 this this DT 746 751 study study NN 751 752 , , , 753 755 we we PRP 756 768 investigated investigate VBD 769 772 the the DT 773 783 importance importance NN 784 786 of of IN 787 789 PI PI NNP 790 798 3-kinase 3-kinase NNP 799 801 in in IN 802 814 TCR-directed tcr-directed JJ 815 821 T-cell T-cell NNP 822 832 activation activation NN 833 838 using use VBG 839 848 activated activate VBN 849 851 or or CC 852 862 inhibitory inhibitory JJ 863 871 versions version NNS 872 874 of of IN 875 877 PI PI NNP 878 886 3-kinase 3-kinase NNP 886 887 . . . 888 895 RESULTS results NNS 895 896 : : : 897 904 Certain certain JJ 905 912 aspects aspect NNS 913 915 of of IN 916 919 TCR TCR NNP 920 929 responses response NNS 930 934 such such JJ 935 937 as as IN 938 941 the the DT 942 951 induction induction NN 952 954 of of IN 955 970 transcriptional transcriptional JJ 971 979 activity activity NN 980 982 of of IN 983 986 AP1 ap1 NN 987 990 and and CC 991 996 serum serum NN 997 1005 response response NN 1006 1012 factor factor NN 1013 1017 were be VBD 1018 1021 not not RB 1022 1030 affected affect VBN 1031 1033 by by IN 1034 1044 expression expression NN 1045 1047 of of IN 1048 1051 the the DT 1052 1058 mutant mutant JJ 1059 1064 forms form NNS 1065 1067 of of IN 1068 1070 PI PI NNP 1071 1079 3-kinase 3-kinase NNP 1079 1080 . . . 1081 1083 We we PRP 1084 1089 found find VBD 1089 1090 , , , 1091 1098 however however RB 1098 1099 , , , 1100 1104 that that IN 1105 1107 PI PI NNP 1108 1116 3-kinase 3-kinase NNP 1117 1127 profoundly profoundly RB 1128 1138 influenced influence VBD 1139 1142 the the DT 1143 1158 transactivation transactivation NN 1159 1167 capacity capacity NN 1168 1170 of of IN 1171 1172 ‘ ` `` 1172 1179 nuclear nuclear JJ 1180 1186 factor factor NN 1187 1189 of of IN 1190 1199 activated activate VBN 1200 1201 T t NN 1202 1207 cells cell NNS 1207 1208 ’ ' POS 1209 1210 ( ( ( 1210 1215 NF-AT NF-AT NNP 1215 1216 ) ) ) 1217 1225 elicited elicit VBN 1226 1228 by by IN 1229 1232 the the DT 1233 1236 TCR TCR NNP 1236 1237 : : : 1238 1248 expression expression NN 1249 1251 of of IN 1252 1254 an an DT 1255 1264 activated activated JJ 1265 1269 form form NN 1270 1272 of of IN 1273 1275 PI PI NNP 1276 1284 3-kinase 3-kinase NNP 1285 1294 inhibited inhibit VBD 1295 1307 TCR-mediated tcr-mediated JJ 1308 1313 NF-AT NF-AT NNP 1314 1323 responses response NNS 1323 1324 , , , 1325 1332 whereas whereas IN 1333 1343 expression expression NN 1344 1346 of of IN 1347 1348 a a DT 1349 1357 dominant dominant JJ 1358 1366 negative negative JJ 1367 1373 mutant mutant NN 1374 1376 of of IN 1377 1379 PI PI NNP 1380 1388 3-kinase 3-kinase NNP 1389 1397 potently potently RB 1398 1406 enhanced enhance VBD 1407 1421 TCR-controlled tcr-controlled JJ 1422 1427 NF-AT nf-at NN 1428 1437 induction induction NN 1437 1438 . . . 1439 1444 These these DT 1445 1452 effects effect NNS 1453 1455 of of IN 1456 1458 PI PI NNP 1459 1467 3-kinase 3-kinase NNP 1468 1472 were be VBD 1473 1476 not not RB 1477 1485 mediated mediate VBN 1486 1488 by by IN 1489 1499 previously previously RB 1500 1510 identified identify VBN 1511 1513 PI PI NNP 1514 1522 3-kinase 3-kinase NNP 1523 1532 effectors effector NNS 1532 1533 , , , 1534 1538 such such JJ 1539 1541 as as IN 1542 1549 protein protein NN 1550 1556 kinase kinase NNP 1557 1558 B B NNP 1558 1559 , , , 1560 1561 a a DT 1562 1570 positive positive JJ 1571 1580 regulator regulator NN 1581 1583 of of IN 1584 1586 PI PI NNP 1587 1595 3-kinase 3-kinase NNP 1595 1596 , , , 1597 1599 or or CC 1600 1603 the the DT 1604 1610 GTPase GTPase NNP 1611 1614 Rac Rac NNP 1614 1615 , , , 1616 1619 and and CC 1620 1623 are be VBP 1624 1633 therefore therefore RB 1634 1640 likely likely JJ 1641 1643 to to TO 1644 1651 involve involve VB 1652 1653 a a DT 1654 1659 novel novel JJ 1659 1660 , , , 1661 1663 as as IN 1664 1667 yet yet RB 1668 1675 unknown unknown JJ 1675 1676 , , , 1677 1685 effector effector NN 1686 1694 molecule molecule NN 1694 1695 . . . 1696 1707 CONCLUSIONS conclusions NNS 1707 1708 : : : 1709 1712 Our our PRP$ 1713 1720 results result NNS 1721 1730 establish establish VBP 1731 1735 that that IN 1736 1738 PI PI NNP 1739 1747 3-kinase 3-kinase NNP 1748 1751 can can MD 1752 1756 both both CC 1757 1767 positively positively RB 1768 1771 and and CC 1772 1782 negatively negatively RB 1783 1791 regulate regulate VB 1792 1798 T-cell t-cell NN 1799 1807 function function NN 1807 1808 , , , 1809 1812 and and CC 1813 1820 uncover uncover VBP 1821 1822 a a DT 1823 1833 previously previously RB 1834 1846 unrecognized unrecognized JJ 1847 1855 function function NN 1856 1859 for for IN 1860 1862 PI PI NNP 1863 1871 3-kinase 3-kinase NNP 1872 1874 in in IN 1875 1876 T t NN 1877 1882 cells cell NNS 1883 1885 as as IN 1886 1887 a a DT 1888 1897 selective selective JJ 1898 1906 negative negative JJ 1907 1916 regulator regulator NN 1917 1919 of of IN 1920 1934 TCR-signalling tcr-signalling JJ 1935 1941 events event NNS 1942 1945 and and CC 1946 1955 therefore therefore RB 1956 1958 as as IN 1959 1960 a a DT 1961 1972 determinant determinant NN 1973 1975 of of IN 1976 1982 T-cell t-cell NN 1983 1994 homeostasis homeostasis NN 1994 1995 . . .