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

Jens Geginat, Barbara Clissi, Monica Moro, Paolo Dellabona, Jeffrey R. Bender, Ruggero Pardi

Research output: Contribution to journalArticlepeer-review

Abstract

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-κB 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.

Original languageEnglish
Pages (from-to)1136-1144
Number of pages9
JournalEuropean Journal of Immunology
Volume30
Issue number4
DOIs
Publication statusPublished - 2000

Keywords

  • Cell proliferation
  • Co-stimulatory molecule
  • Cyclosporin A
  • IL-2
  • T lymphocyte

ASJC Scopus subject areas

  • Immunology

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