0 10 Modulation modulation NN 11 13 of of IN 14 18 CD28 cd28 NN 19 29 expression expression NN 29 30 : : : 31 39 distinct distinct JJ 40 50 regulatory regulatory JJ 51 59 pathways pathway NNS 60 66 during during IN 67 77 activation activation NN 78 81 and and CC 82 93 replicative replicative JJ 94 104 senescence senescence NN 104 105 . . . 107 110 The the DT 111 124 costimulatory costimulatory JJ 125 133 molecule molecule NN 134 138 CD28 cd28 NN 139 142 has have VBZ 143 144 a a DT 145 155 restricted restricted JJ 156 162 tissue tissue NN 163 175 distribution distribution NN 176 179 and and CC 180 182 is be VBZ 183 192 expressed express VBN 193 195 on on IN 196 197 T t NN 198 203 cells cell NNS 204 207 and and CC 208 212 some some DT 213 225 plasmacytoma plasmacytoma NN 226 231 cells cell NNS 231 232 . . . 233 241 Although although IN 242 246 CD28 cd28 NN 247 249 is be VBZ 250 264 constitutively constitutively RB 265 274 expressed express VBN 274 275 , , , 276 279 its its PRP$ 280 290 expression expression NN 291 293 is be VBZ 294 305 transiently transiently RB 306 320 down-regulated down-regulate VBN 321 330 following follow VBG 331 332 T t NN 333 337 cell cell NN 338 348 activation activation NN 349 352 and and CC 353 361 declines decline VBZ 362 375 progressively progressively RB 376 380 with with IN 381 383 in in FW 384 389 vitro vitro FW 390 400 senescence senescence NN 400 401 . . . 402 404 In in FW 405 409 vivo vivo FW 409 410 , , , 411 415 CD8+ cd8+ JJ 416 417 T t NN 418 423 cells cell NNS 424 427 and and CC 427 428 , , , 429 433 less less RBR 434 444 frequently frequently RB 444 445 , , , 446 450 CD4+ cd4+ JJ 451 452 T t NN 453 458 cells cell NNS 459 462 may may MD 463 473 completely completely RB 474 478 lose lose VB 479 483 CD28 cd28 NN 484 491 surface surface NN 492 502 expression expression NN 503 509 during during IN 510 517 chronic chronic JJ 518 528 infections infection NNS 529 532 and and CC 533 537 with with IN 538 543 aging aging NN 543 544 . . . 545 549 This this DT 550 560 correlates correlate VBZ 561 565 with with IN 566 573 changes change NNS 574 576 of of IN 577 584 nuclear nuclear JJ 585 600 protein-binding protein-binding JJ 601 611 activities activity NNS 612 614 to to TO 615 618 two two CD 619 625 motifs motif NNS 625 626 , , , 627 631 site site NN 632 637 alpha alpha NN 638 641 and and CC 642 646 beta beta NN 646 647 , , , 648 654 within within IN 655 658 the the DT 659 663 CD28 cd28 NN 664 671 minimal minimal JJ 672 680 promoter promoter NN 680 681 . . . 682 686 Both both CC 687 693 alpha- alpha- NN 694 697 and and CC 698 708 beta-bound beta-bound JJ 709 718 complexes complex NNS 719 722 are be VBP 723 728 found find VBN 729 733 only only RB 734 736 in in IN 737 745 lymphoid lymphoid JJ 746 753 tissues tissue NNS 753 754 , , , 755 757 in in IN 758 763 CD28+ cd28+ JJ 764 765 T t NN 766 771 cells cell NNS 771 772 , , , 773 776 and and CC 777 779 in in IN 780 784 some some DT 785 796 transformed transform VBN 797 798 B b NN 799 804 cells cell NNS 804 805 . . . 806 811 These these DT 812 821 complexes complex NNS 822 825 are be VBP 826 838 coordinately coordinately RB 839 848 expressed express VBN 849 855 except except IN 856 862 during during IN 863 874 replicative replicative JJ 875 885 senescence senescence NN 885 886 , , , 887 892 which which WDT 893 895 is be VBZ 896 909 characterized characterize VBN 910 912 by by IN 913 916 the the DT 917 932 down-modulation down-modulation NN 933 935 of of IN 936 940 site site NN 941 946 beta- beta- NN 947 950 but but CC 951 954 not not RB 955 959 site site NN 960 973 alpha-binding alpha-binding JJ 974 984 activities activity NNS 984 985 . . . 986 988 In in IN 989 997 contrast contrast NN 997 998 , , , 999 1000 T t NN 1001 1005 cell cell NN 1006 1016 activation activation NN 1017 1024 induces induce VBZ 1025 1026 a a DT 1027 1035 parallel parallel JJ 1036 1043 decline decline NN 1044 1046 in in IN 1047 1051 both both CC 1052 1056 site site NN 1057 1063 alpha- alpha- NN 1064 1067 and and CC 1068 1080 beta-binding beta-binding JJ 1081 1091 activities activity NNS 1091 1092 . . . 1093 1097 CD4+ cd4+ JJ 1098 1101 and and CC 1102 1106 CD8+ cd8+ JJ 1107 1108 T t NN 1109 1114 cells cell NNS 1115 1121 differ differ VBP 1122 1124 in in IN 1125 1130 their their PRP$ 1131 1143 beta-binding beta-binding JJ 1144 1152 profiles profile NNS 1152 1153 , , , 1154 1159 which which WDT 1160 1163 may may MD 1164 1171 explain explain VB 1172 1175 the the DT 1176 1180 more more RBR 1181 1191 pronounced pronounced JJ 1192 1207 down-regulation down-regulation NN 1208 1210 of of IN 1211 1215 CD28 cd28 NN 1216 1218 in in IN 1219 1228 senescent senescent JJ 1229 1233 CD8+ cd8+ JJ 1234 1235 T t NN 1236 1241 cells cell NNS 1241 1242 . . . 1243 1245 In in FW 1246 1250 vivo vivo FW 1251 1259 expanded expand VBN 1260 1272 CD4+CD28null cd4+cd28null JJ 1273 1276 and and CC 1277 1289 CD8+CD28null cd8+cd28null JJ 1290 1291 T t NN 1292 1297 cells cell NNS 1298 1307 uniformly uniformly RB 1308 1312 lack lack VBP 1313 1319 alpha- alpha- NN 1320 1323 and and CC 1324 1329 beta- beta- NN 1330 1335 bound bind VBD 1336 1345 complexes complex NNS 1345 1346 , , , 1347 1357 resembling resemble VBG 1358 1361 the the DT 1362 1369 pattern pattern NN 1370 1374 seen see VBN 1375 1377 in in IN 1378 1389 chronically chronically RB 1390 1399 activated activate VBN 1400 1405 cells cell NNS 1406 1409 and and CC 1410 1413 not not RB 1414 1416 of of IN 1417 1426 senescent senescent JJ 1427 1432 cells cell NNS 1432 1433 . . .