The identification of a novel T cell activation state controlled by a diabetogenic gene

被引:12
作者
Moore, JK
Scheinman, RI
Bellgrau, D
机构
[1] Univ Colorado, Hlth Sci Ctr, Barbara Davis Ctr Childhood Diabet, Sch Med,Dept Immunol, Denver, CO 80262 USA
[2] Univ Colorado, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci, Denver, CO 80262 USA
关键词
D O I
10.4049/jimmunol.166.1.241
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The cyclin-dependent kinase inhibitor p27(kip) regulates the cell cycle at the G(1)-S phase restriction point. S phase entry and cell cycle commitment in peripheral T cells requires p27(kip) degradation, normally initiated by the receipt of costimulatory signals such as those provided by B7.1 or IL-2. We have previously reported that T cells from BioBreeding (BB)-diabetes-prone (DP) rats exhibit decreased costimulatory requirements for activation and cell cycle entry. In the present study, we find that peripheral T cell subsets from BB-DP rats demonstrate activation-like characteristics, including significantly reduced levels of p27(kip) as well as increased levels of proliferating cell nuclear Ag (PCNA), Since our previous studies have established that expression of extracellular activation markers are relatively low in unmanipulated peripheral BB-DP T cells; this p27(low) PCNA(high) phenotype represents a novel activation state, Analyses of T cell subsets from congenic rats demonstrate that this phenotype segregates with the lyp diabetogenic locus and that the p27(low) pCNA(high) phenotype is T cell specific. This p27(low) PCNA(high) phenotype is not seen in medullary thymocytes, but appears abruptly in the recent thymic emigrant population, suggesting that the lyp locus does not act directly on cell cycle regulators but rather alters the interaction between T cells and the peripheral environment, These results provide a biochemical basis for costimulation-independent activation and suggest a mechanism whereby a diabetes susceptibility gene contributes to disease development.
引用
收藏
页码:241 / 248
页数:8
相关论文
共 72 条
  • [11] A THEORY OF SELF-NONSELF DISCRIMINATION
    BRETSCHER, P
    COHN, M
    [J]. SCIENCE, 1970, 169 (3950) : 1042 - +
  • [12] Survival of mature CD4 T lymphocytes is dependent on major histocompatibility complex class II-expressing dendritic cells
    Brocker, T
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1997, 186 (08) : 1223 - 1232
  • [13] AN RT6A GENE IS TRANSCRIBED AND TRANSLATED IN LYMPHOPENIC DIABETES-PRONE BB RATS
    CRISA, L
    SARKAR, P
    WAITE, DJ
    FRIEDRICH, FH
    KOCHNOLTE
    RAJAN, TV
    MORDES, JP
    HANDLER, ES
    THIELE, HG
    ROSSINI, AA
    GREINER, DL
    [J]. DIABETES, 1993, 42 (05) : 688 - 695
  • [14] AUTOIMMUNE DIABETES-MELLITUS IN THE BB RAT
    CRISA, L
    MORDES, JP
    ROSSINI, AA
    [J]. DIABETES-METABOLISM REVIEWS, 1992, 8 (01): : 9 - 37
  • [15] INACTIVATION OF A CDK2 INHIBITOR DURING INTERLEUKIN 2-INDUCED PROLIFERATION OF HUMAN T-LYMPHOCYTES
    FIRPO, EJ
    KOFF, A
    SOLOMON, MJ
    ROBERTS, JM
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1994, 14 (07) : 4889 - 4901
  • [16] Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts
    Goldrath, AW
    Bevan, MJ
    [J]. IMMUNITY, 1999, 11 (02) : 183 - 190
  • [17] GREINER DL, 1986, J IMMUNOL, V136, P148
  • [18] GROEN H, 1989, THYMUS, V14, P145
  • [19] COMPARISON OF 3 QUANTITATION METHODS FOR PCNA IMMUNOSTAINING - APPLICABILITY AND RELATION TO SURVIVAL IN 83 ASTROCYTIC NEOPLASMS
    HAAPASALO, HK
    SALLINEN, PK
    HELEN, PT
    RANTALA, IS
    HELIN, HJ
    ISOLA, JJ
    [J]. JOURNAL OF PATHOLOGY, 1993, 171 (03) : 207 - 214
  • [20] Cyclin-dependent kinases at the G1-S transition of the mammalian cell cycle
    Hengstschläger, M
    Braun, K
    Soucek, T
    Miloloza, A
    Hengstschläger-Ottnad, E
    [J]. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH, 1999, 436 (01) : 1 - 9