Rudimentary TCR Signaling Triggers Default IL-10 Secretion by Human Th1 Cells
| Autor: | Arthur A. Vandenbark, Tohru Yoshioka, Yuan K. Chou, Joseph Kim, Masayuki Ikeda, Halina Offner, Gregory G. Burrows, Dennis Bourdette, Justin W. Chang, Nicole Culbertson, Chunhe Wang, Charles N. Allen, Deborah A. Lewinsohn, David M. Lewinsohn, Thomas P. Finn |
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| Rok vydání: | 2001 |
| Předmět: |
Multiple Sclerosis
T cell Immunology Cell Fusion Proteins bcr-abl Receptors Antigen T-Cell Biology Ligands medicine Humans Immunology and Allergy Secretion Calcium Signaling HLA-DR2 Antigen Kinase activity T-cell receptor Myelin Basic Protein Th1 Cells Peptide Fragments Clone Cells Interleukin-10 Myelin basic protein Cell biology Interleukin 10 medicine.anatomical_structure Biochemistry Genes T-Cell Receptor beta biology.protein Phosphorylation Signal Transduction |
| Zdroj: | The Journal of Immunology. 167:4386-4395 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Understanding the process of inducing T cell activation has been hampered by the complex interactions between APC and inflammatory Th1 cells. To dissociate Ag-specific signaling through the TCR from costimulatory signaling, rTCR ligands (RTL) containing the α1 and β1 domains of HLA-DR2b (DRA*0101:DRB1*1501) covalently linked with either the myelin basic protein peptide 85–99 (RTL303) or CABL-b3a2 (RTL311) peptides were constructed to provide a minimal ligand for peptide-specific TCRs. When incubated with peptide-specific Th1 cell clones in the absence of APC or costimulatory molecules, only the cognate RTL induced partial activation through the TCR. This partial activation included rapid TCR ζ-chain phosphorylation, calcium mobilization, and reduced extracellular signal-related kinase activity, as well as IL-10 production, but not proliferation or other obvious phenotypic changes. On restimulation with APC/peptide, the RTL-pretreated Th1 clones had reduced proliferation and secreted less IFN-γ; IL-10 production persisted. These findings reveal for the first time the rudimentary signaling pattern delivered by initial engagement of the external TCR interface, which is further supplemented by coactivation molecules. Activation with RTLs provides a novel strategy for generating autoantigen-specific bystander suppression useful for treatment of complex autoimmune diseases. |
| Databáze: | OpenAIRE |
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