p27kip1 functions as an anergy factor inhibiting interleukin 2 transcription and clonal expansion of alloreactive human and mouse helper T lymphocytes.
Although recent in vitro studies have begun to decipher the molecular events that characterize the anergic state, their in vivo biologic relevance and potential clinical importance remain unclear. Here, using anergic human T-cell clones and tolerant alloreactive mouse T cells that do not induce graft-versus-host disease, we show that p27kip1 cyclin-dependent kinase inhibitor is an essential regulator responsible for the blockade of clonal expansion of anergic T cells in vitro and in vivo. Moreover, in anergic cells, p27kip1 associates with the c-Jun co-activator JAB1, resulting in defective transactivation of AP-1 and interleukin 2 transcription. Therefore, pharmacological agents that upregulate the expression of or prevent the degradation of p27kip1 during antigen recognition should be part of new therapeutic strategies to induce antigen-specific T-cell unresponsiveness.
Boussiotis
V A
VA
Department of Adult Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. vassiliki_boussiotis@dfci.harvard.edu
Freeman
G J
GJ
Taylor
P A
PA
Berezovskaya
A
A
Grass
I
I
Blazar
B R
BR
Nadler
L M
LM
D000818:Animals; D019556:COS Cells; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D017635:Clonal Anergy; D002999:Clone Cells; D056742:Cyclin D2; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D016193:G1 Phase; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology*; D014158:Transcription, Genetic; D014162:Transfection; D025521:Tumor Suppressor Proteins
C080336:CCND2 protein, human; C486196:Ccnd2 protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D056742:Cyclin D2; D016213:Cyclins; D007376:Interleukin-2; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases