CD28 and LFA-1 contribute to cyclosporin A-resistant T cell growth by stabilizing the IL-2 mRNA through distinct signaling pathways.
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.
Geginat
J
J
Department of Molecular Pathology and Medicine, Scientific Institute San Raffaele-DIBIT, Milano, Italy.
Clissi
B
B
Moro
M
M
Dellabona
P
P
Bender
J R
JR
Pardi
R
R
D015703:Antigens, CD / Q000276:immunology; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000276:immunology*; D019703:Calcineurin / Q000502:physiology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D003599:Cytoskeleton / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004357:Drug Synergism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D018089:Superantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D015703:Antigens, CD; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018089:Superantigens; D014157:Transcription Factors; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine; D020928:Mitogen-Activated Protein Kinases; D019703:Calcineurin