Peptide-Induced Negative Selection of Thymocytes Activates Transcription of an NF-ΚB Inhibitor

• Published in: Molecular cell 2002-03, Vol.9 (3), p.637-648
• Main Authors: Fiorini, Emma, Schmitz, Ingo, Marissen, Wilfred E., Osborn, Stephanie L., Touma, Maki, Sasada, Tetsuro, Reche, Pedro A., Tibaldi, Elena V., Hussey, Rebecca E., Kruisbeek, Ada M., Reinherz, Ellis L., Clayton, Linda K.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Cell Fractionation; Cell Separation; Flow Cytometry; Genes, Reporter; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mice, Transgenic; Molecular Sequence Data; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Peptides - metabolism; Proteins - chemistry; Proteins - genetics; Proteins - metabolism; Receptors, Antigen, T-Cell - physiology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Sequence Alignment; T-Lymphocytes - physiology; Thymus Gland - cytology; Transcription, Genetic; Transduction, Genetic
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/S1097-2765(02)00469-0

Negative selection eliminates thymocytes bearing autoreactive T cell receptors (TCR) via an apoptotic mechanism. We have cloned an inhibitor of NF-ΚB, IΚBNS, which is rapidly expressed upon TCR-triggered but not dexamethasone- or γ irradiation-stimulated thymocyte death. The predicted protein contains seven ankyrin repeats and is homologous to IΚB family members. In class I and class II MHC-restricted TCR transgenic mice, transcription of IΚBNS is stimulated by peptides that trigger negative selection but not by those inducing positive selection (i.e., survival) or nonselecting peptides. IΚBNS blocks transcription from NF-ΚB reporters, alters NF-ΚB electrophoretic mobility shifts, and interacts with NF-ΚB proteins in thymic nuclear lysates following TCR stimulation. Retroviral transduction of IΚBNS in fetal thymic organ culture enhances TCR-triggered cell death consistent with its function in selection.