Maintenance of human T cell anergy: blocking of IL-2 gene transcription by activated Rap1.
In the absence of costimulation, T cells activated through their antigen receptor become unresponsive (anergic) and do not transcribe the gene encoding interleukin-2 (IL-2) when restimulated with antigen. Anergic alloantigen-specific human T cells contained phosphorylated Cbl that coimmunoprecipitated with Fyn. The adapter protein CrkL was associated with both phosphorylated Cbl ... and the guanidine nucleotide-releasing factor C3G, which catalyzes guanosine triphosphate (GTP) exchange on Rap1. Active Rap1 (GTP-bound form) was present in anergic cells. Forced expression of low amounts of Rap1-GTP in Jurkat T cells recapitulated the anergic defect and blocked T cell antigen receptor (TCR)- and CD28-mediated IL-2 gene transcription. Therefore, Rap1 functions as a negative regulator of TCR-mediated IL-2 gene transcription and may be responsible for the specific defect in IL-2 production in T cell anergy.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Antigens, CD28, Clonal Anergy, GTP-Binding Proteins, Gene Expression Regulation, Guanine Nucleotide Exchange Factors, Guanosine Triphosphate, Humans, Interleukin-2, Jurkat Cells, Nuclear Proteins, Phosphorylation, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Proto-Oncogene Proteins c-fyn, Receptors, Antigen, T-Cell, Recombinant Fusion Proteins, Signal Transduction, T-Lymphocytes, Transcription, Genetic, Transfection, Ubiquitin-Protein Ligases, rap GTP-Binding Proteins, ras Guanine Nucleotide Exchange Factors, ras Proteins, src Homology Domains
Adaptor Proteins, Signal Transducing, Antigens, CD28, Clonal Anergy, GTP-Binding Proteins, Gene Expression Regulation, Guanine Nucleotide Exchange Factors, Guanosine Triphosphate, Humans, Interleukin-2, Jurkat Cells, Nuclear Proteins, Phosphorylation, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Proto-Oncogene Proteins c-fyn, Receptors, Antigen, T-Cell, Recombinant Fusion Proteins, Signal Transduction, T-Lymphocytes, Transcription, Genetic, Transfection, Ubiquitin-Protein Ligases, rap GTP-Binding Proteins, ras Guanine Nucleotide Exchange Factors, ras Proteins, src Homology Domains
Science
Date: Oct. 03, 1997
PubMed ID: 9311917
View in: Pubmed Google Scholar
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