1. Epitope-specific engagement of the protein tyrosine phosphatase CD45 induces tumor necrosis factor-α gene expression via transcriptional mechanisms
- Author
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Alain Sauty, Enric Espel, Olivier Estoppey, Véronique Menoud, François Spertini, and P. C. Frei
- Subjects
Transcription, Genetic ,T-Lymphocytes ,T cell ,Immunology ,Protein tyrosine phosphatase ,Biology ,Lymphocyte Activation ,Epitope ,Epitopes ,FYN ,Gene expression ,Transcriptional regulation ,medicine ,Humans ,Immunology and Allergy ,RNA, Messenger ,Protein Synthesis Inhibitors ,Regulation of gene expression ,Tumor Necrosis Factor-alpha ,T-cell receptor ,Antibodies, Monoclonal ,Molecular biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Leukocyte Common Antigens ,Protein Tyrosine Phosphatases - Abstract
The common leukocyte antigen CD45 plays a central role in T cell activation in coupling the T cell receptor (TCR) to the phosphatidylinositol pathway via interactions with TCR-associated protein tyrosine kinases lck and fyn. We here demonstrate that engagement of CD45 by monoclonal antibodies (mAb) on activated T cells induces tumor necrosis factor (TNF)-alpha as well as TNF-beta, interleukin (IL)-2 and IL-3 gene expression. When human alloreactive T cells are stimulated with mAb 4B2, which recognizes a determinant common to all CD45 isoforms, a vigorous production of TNF-alpha mRNA was detected, which peaked 2 h later. Anti-CD45 mAb cross-linking was required. In contrast, neither mAb 10G10, which recognizes an epitope distinct from the one recognized by mAb 4B2, nor mAb UCHL-1, a CD45RO-specific antibody, induced any significant increase in TNF-alpha transcription. Nuclear run-on transcription assays demonstrated that CD45 cross-linking caused transcriptional activation of the TNF-alpha gene. De novo protein synthesis was not required, since incubation with cycloheximide (CHX) did not block transcriptional activation. CHX in contrast up-regulated TNF-alpha gene expression and increased transcript half-life, an effect that was under control of post-transcriptional mechanisms. Engagement of CD45 by itself did not affect transcript stability. CD45 ligation resulted in TNF-alpha secretion. These results indicate that in addition to its role in TCR/CD3-mediated T cell activation, CD45, in an epitope-specific manner, may act as a primary signaling molecule, leading to the transcriptional regulation and secretion of a major pro-inflammatory cytokine.
- Published
- 1996