0 3 The the DT 4 15 development development NN 16 18 of of IN 19 31 functionally functionally RB 32 42 responsive responsive JJ 43 44 T t NN 45 50 cells cell NNS 50 51 . . . 53 56 The the DT 57 61 work work NN 62 70 reviewed review VBN 71 73 in in IN 74 78 this this DT 79 86 article article NN 87 96 separates separate VBZ 97 98 T t NN 99 103 cell cell NN 104 115 development development NN 116 120 into into IN 121 125 four four CD 126 132 phases phase NNS 132 133 . . . 134 139 First first JJ 140 142 is be VBZ 143 145 an an DT 146 155 expansion expansion NN 156 161 phase phase NN 162 167 prior prior JJ 168 170 to to TO 171 174 TCR TCR NNP 175 188 rearrangement rearrangement NN 188 189 , , , 190 195 which which WDT 196 203 appears appear VBZ 204 206 to to TO 207 209 be be VB 210 220 correlated correlate VBN 221 225 with with IN 226 237 programming programming NN 238 240 of of IN 241 243 at at IN 244 249 least least JJS 250 254 some some DT 255 263 response response NN 264 269 genes gene NNS 270 273 for for IN 274 286 inducibility inducibility NN 286 287 . . . 288 292 This this DT 293 298 phase phase NN 299 302 can can MD 303 308 occur occur VB 309 311 to to TO 312 316 some some DT 317 323 extent extent NN 324 331 outside outside IN 332 334 of of IN 335 338 the the DT 339 345 thymus thymus NN 345 346 . . . 347 354 However however RB 354 355 , , , 356 359 the the DT 360 368 profound profound JJ 369 370 T t NN 371 375 cell cell NN 376 383 deficit deficit NN 384 386 of of IN 387 391 nude nude JJ 392 396 mice mouse NNS 397 406 indicates indicate VBZ 407 411 that that IN 412 415 the the DT 416 422 thymus thymus NN 423 425 is be VBZ 426 428 by by IN 429 432 far far RB 433 436 the the DT 437 441 most most RBS 442 448 potent potent JJ 449 453 site site NN 454 457 for for IN 458 466 inducing induce VBG 467 470 the the DT 471 480 expansion expansion NN 481 484 per per FW 485 487 se se FW 487 488 , , , 489 493 even even RB 494 496 if if IN 497 502 other other JJ 503 508 sites site NNS 509 512 can can MD 513 519 induce induce VB 520 524 some some DT 525 533 response response NN 534 545 acquisition acquisition NN 545 546 . . . 547 553 Second second JJ 554 556 is be VBZ 557 558 a a DT 559 569 controlled controlled JJ 570 575 phase phase NN 576 578 of of IN 579 582 TCR TCR NNP 583 587 gene gene NN 588 601 rearrangement rearrangement NN 601 602 . . . 603 606 The the DT 607 614 details detail NNS 615 617 of of IN 618 621 the the DT 622 632 regulatory regulatory JJ 633 642 mechanism mechanism NN 643 647 that that WDT 648 655 selects select VBZ 656 666 particular particular JJ 667 671 loci locus NNS 672 675 for for IN 676 689 rearrangement rearrangement NN 690 693 are be VBP 694 699 still still RB 700 703 not not RB 704 709 known know VBN 709 710 . . . 711 713 It it PRP 714 719 seems seem VBZ 720 724 that that IN 725 728 the the DT 729 742 rearrangement rearrangement NN 743 745 of of IN 746 749 the the DT 750 753 TCR TCR NNP 754 759 gamma gamma NN 760 764 loci locus NNS 765 767 in in IN 768 771 the the DT 772 777 gamma gamma NN 778 783 delta delta NN 784 791 lineage lineage NN 792 795 may may MD 796 799 not not RB 800 806 always always RB 807 811 take take VB 812 817 place place NN 818 820 at at IN 821 822 a a DT 823 836 developmental developmental JJ 837 842 stage stage NN 843 851 strictly strictly RB 852 862 equivalent equivalent JJ 863 865 to to TO 866 869 the the DT 870 883 rearrangement rearrangement NN 884 886 of of IN 887 890 TCR TCR NNP 891 895 beta beta NN 896 898 in in IN 899 902 the the DT 903 908 alpha alpha NN 909 913 beta beta NN 914 921 lineage lineage NN 921 922 , , , 923 926 and and CC 927 929 it it PRP 930 932 is be VBZ 933 936 not not RB 937 942 clear clear JJ 943 947 just just RB 948 951 how how WRB 952 957 early early RB 958 961 the the DT 962 965 two two CD 966 974 lineages lineage NNS 975 982 diverge diverge VBP 982 983 . . . 984 986 In in IN 987 990 the the DT 991 994 TCR TCR NNP 995 1000 alpha alpha NN 1001 1005 beta beta NN 1006 1013 lineage lineage NN 1013 1014 , , , 1015 1022 however however RB 1022 1023 , , , 1024 1027 the the DT 1028 1033 final final JJ 1034 1038 gene gene NN 1039 1052 rearrangement rearrangement NN 1053 1059 events event NNS 1060 1063 are be VBP 1064 1075 accompanied accompany VBN 1076 1078 by by IN 1079 1084 rapid rapid JJ 1085 1098 proliferation proliferation NN 1099 1102 and and CC 1103 1105 an an DT 1106 1118 interruption interruption NN 1119 1121 in in IN 1122 1130 cellular cellular JJ 1131 1139 response response NN 1140 1144 gene gene NN 1145 1157 inducibility inducibility NN 1157 1158 . . . 1159 1162 The the DT 1163 1167 loss loss NN 1168 1170 of of IN 1171 1183 conventional conventional JJ 1184 1198 responsiveness responsiveness NN 1199 1201 is be VBZ 1202 1210 probably probably RB 1211 1217 caused cause VBN 1218 1220 by by IN 1221 1232 alterations alteration NNS 1233 1235 at at IN 1236 1239 the the DT 1240 1245 level level NN 1246 1248 of of IN 1249 1258 signaling signaling NN 1258 1259 , , , 1260 1263 and and CC 1264 1267 may may MD 1268 1270 be be VB 1271 1272 a a DT 1273 1286 manifestation manifestation NN 1287 1289 of of IN 1290 1293 the the DT 1294 1307 physiological physiological JJ 1308 1313 state state NN 1314 1318 that that WDT 1319 1321 is be VBZ 1322 1323 a a DT 1324 1336 precondition precondition NN 1337 1340 for for IN 1341 1350 selection selection NN 1350 1351 . . . 1352 1357 Third third JJ 1358 1360 is be VBZ 1361 1364 the the DT 1365 1372 complex complex JJ 1373 1380 process process NN 1381 1383 of of IN 1384 1393 selection selection NN 1393 1394 . . . 1395 1402 Whereas whereas IN 1403 1413 peripheral peripheral JJ 1414 1415 T t NN 1416 1421 cells cell NNS 1422 1425 can can MD 1426 1433 undergo undergo VB 1434 1439 forms form NNS 1440 1442 of of IN 1443 1451 positive positive JJ 1452 1461 selection selection NN 1462 1463 ( ( ( 1463 1465 by by IN 1466 1480 antigen-driven antigen-driven JJ 1481 1487 clonal clonal JJ 1488 1497 expansion expansion NN 1497 1498 ) ) ) 1499 1502 and and CC 1503 1511 negative negative JJ 1512 1521 selection selection NN 1522 1523 ( ( ( 1523 1525 by by IN 1526 1534 abortive abortive JJ 1535 1546 stimulation stimulation NN 1547 1554 leading lead VBG 1555 1557 to to TO 1558 1564 anergy anergy NN 1565 1567 or or CC 1568 1573 death death NN 1573 1574 ) ) ) 1574 1575 , , , 1576 1583 neither neither DT 1584 1586 is be VBZ 1587 1594 exactly exactly RB 1595 1598 the the DT 1599 1603 same same JJ 1604 1614 phenomenon phenomenon NN 1615 1619 that that WDT 1620 1626 occurs occur VBZ 1627 1629 in in IN 1630 1633 the the DT 1634 1640 thymic thymic JJ 1641 1647 cortex cortex NN 1647 1648 . . . 1649 1657 Negative negative JJ 1658 1667 selection selection NN 1668 1670 in in IN 1671 1674 the the DT 1675 1681 cortex cortex NN 1682 1689 appears appear VBZ 1690 1692 to to TO 1693 1695 be be VB 1696 1697 a a DT 1698 1706 suicidal suicidal JJ 1707 1716 inversion inversion NN 1717 1719 of of IN 1720 1727 antigen antigen NN 1728 1742 responsiveness responsiveness NN 1742 1743 : : : 1744 1751 instead instead RB 1752 1754 of of IN 1755 1762 turning turn VBG 1763 1765 on on IN 1766 1770 IL-2 il-2 NN 1771 1781 expression expression NN 1781 1782 , , , 1783 1786 the the DT 1787 1796 activated activate VBN 1797 1801 cell cell NN 1802 1810 destroys destroy VBZ 1811 1814 its its PRP$ 1815 1818 own own JJ 1819 1828 chromatin chromatin NN 1828 1829 . . . 1830 1833 The the DT 1834 1839 genes gene NNS 1840 1844 that that WDT 1845 1849 need need VBP 1850 1852 to to TO 1853 1855 be be VB 1856 1863 induced induce VBN 1864 1867 for for IN 1868 1872 this this DT 1873 1881 response response NN 1882 1885 are be VBP 1886 1889 not not RB 1890 1893 yet yet RB 1894 1904 identified identify VBN 1904 1905 , , , 1906 1909 but but CC 1910 1912 it it PRP 1913 1915 is be VBZ 1916 1930 unquestionably unquestionably RB 1931 1932 a a DT 1933 1937 form form NN 1938 1940 of of IN 1941 1951 activation activation NN 1951 1952 . . . 1953 1955 It it PRP 1956 1958 is be VBZ 1959 1970 interesting interesting JJ 1971 1975 that that IN 1976 1978 in in IN 1979 1985 humans human NNS 1986 1989 and and CC 1990 1994 rats rat NNS 1994 1995 , , , 1996 2004 cortical cortical JJ 2005 2015 thymocytes thymocyte NNS 2016 2026 undergoing undergo VBG 2027 2035 negative negative JJ 2036 2045 selection selection NN 2046 2049 can can MD 2050 2055 still still RB 2056 2062 induce induce VB 2063 2068 IL-2R il-2r NN 2069 2074 alpha alpha NN 2075 2085 expression expression NN 2086 2089 and and CC 2090 2094 even even RB 2095 2097 be be VB 2098 2105 rescued rescue VBN 2106 2108 in in FW 2109 2114 vitro vitro FW 2114 2115 , , , 2116 2118 if if IN 2119 2128 exogenous exogenous JJ 2129 2133 IL-2 il-2 NN 2134 2136 is be VBZ 2137 2145 provided provide VBN 2145 2146 . . . 2147 2154 Perhaps perhaps RB 2155 2161 murine murine JJ 2162 2172 thymocytes thymocyte NNS 2173 2176 are be VBP 2177 2183 denied deny VBN 2184 2188 this this DT 2189 2193 form form NN 2194 2196 of of IN 2197 2203 rescue rescue NN 2204 2211 because because IN 2212 2216 they they PRP 2217 2221 shut shut VBD 2222 2225 off off RP 2226 2231 IL-2R il-2r NN 2232 2236 beta beta NN 2237 2242 chain chain NN 2243 2253 expression expression NN 2254 2256 at at IN 2257 2259 an an DT 2260 2267 earlier early JJR 2268 2273 stage stage NN 2274 2276 or or CC 2277 2284 because because IN 2285 2289 they they PRP 2290 2293 may may MD 2294 2296 be be VB 2297 2307 uncommonly uncommonly RB 2308 2313 Bcl-2 bcl-2 NN 2314 2323 deficient deficient JJ 2324 2325 ( ( ( 2325 2328 cf. cf. NN 2329 2336 Sentman Sentman NNP 2337 2339 et et FW 2340 2343 al. al. FW 2343 2344 , , , 2345 2349 1991 1991 CD 2349 2350 ; ; : 2351 2359 Strasser Strasser NNP 2360 2362 et et FW 2363 2366 al. al. FW 2366 2367 , , , 2368 2372 1991 1991 CD 2372 2373 ) ) ) 2373 2374 . . . 2375 2379 Even even RB 2380 2382 so so RB 2382 2383 , , , 2384 2393 medullary medullary JJ 2394 2404 thymocytes thymocyte NNS 2405 2411 remain remain VBP 2412 2414 at at IN 2415 2420 least least JJS 2421 2430 partially partially RB 2431 2442 susceptible susceptible JJ 2443 2445 to to TO 2446 2454 negative negative JJ 2455 2464 selection selection NN 2465 2469 even even RB 2470 2472 as as IN 2473 2477 they they PRP 2478 2486 continue continue VBP 2487 2489 to to TO 2490 2496 mature mature VB 2497 2498 . . .