10760803

pubmed:Citation

4

In clinical transplantation, the occurrence of cyclosporin A (CsA)-resistant production of IL-2 in vitro correlates with graft rejection in vivo. In this study we investigated the role of the costimulatory molecules CD28 and LFA-1 in this process in the setting of TCR-induced proliferation of primary T lymphocytes in vitro. Co-stimulation with ICAM-1 and B7.2 led to strong and CsA-resistant proliferation, which was found to be largely IL-2 dependent. All of the known calcineurin-dependent events, such as induction of NF-AT and NF-kappaB or stress-activated protein kinase activation, were markedly modulated by CsA independently of costimulation. In contrast, both ICAM-1 and B7.2 enhanced the half-life of the inducible IL-2 transcript in a CsA-resistant manner. LFA-1- but not CD28-induced IL-2 mRNA stabilization required the integrity of the actin-based cytoskeleton, suggesting that the two costimulatory molecules impact on qualitatively different signaling pathways. This is further suggested by the demonstration that LFA-1 and CD28 acted synergistically to confer CsA resistance in a model of co-stimulation using superantigen-pulsed dendritic cells. We propose that IL-2 transcript accumulation and subsequent T cell proliferation at the low transcriptional rate imposed by CsA are the result of co-stimulation-dependent stabilization of IL-2 mRNA.

eng

IM

MEDLINE

0014-2980

Print

NLM

1136-44

pubmed-meshheading:10760803-Antigens, CD, pubmed-meshheading:10760803-Antigens, CD28, pubmed-meshheading:10760803-Antigens, CD86, pubmed-meshheading:10760803-Calcineurin, pubmed-meshheading:10760803-Cells, Cultured, pubmed-meshheading:10760803-Cyclosporine, pubmed-meshheading:10760803-Cytoskeleton, pubmed-meshheading:10760803-DNA-Binding Proteins, pubmed-meshheading:10760803-Dendritic Cells, pubmed-meshheading:10760803-Drug Synergism, pubmed-meshheading:10760803-Humans, pubmed-meshheading:10760803-Intercellular Adhesion Molecule-1, pubmed-meshheading:10760803-Interleukin-2, pubmed-meshheading:10760803-Lymphocyte Activation, pubmed-meshheading:10760803-Lymphocyte Function-Associated Antigen-1, pubmed-meshheading:10760803-Membrane Glycoproteins, pubmed-meshheading:10760803-Mitogen-Activated Protein Kinases, pubmed-meshheading:10760803-NF-kappa B, pubmed-meshheading:10760803-NFATC Transcription Factors, pubmed-meshheading:10760803-Nuclear Proteins, pubmed-meshheading:10760803-Promoter Regions, Genetic, pubmed-meshheading:10760803-Protein Binding, pubmed-meshheading:10760803-RNA, Messenger, pubmed-meshheading:10760803-RNA Stability, pubmed-meshheading:10760803-Signal Transduction, pubmed-meshheading:10760803-Superantigens, pubmed-meshheading:10760803-T-Lymphocytes, pubmed-meshheading:10760803-Transcription Factors

CD28 and LFA-1 contribute to cyclosporin A-resistant T cell growth by stabilizing the IL-2 mRNA through distinct signaling pathways.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't