Peptide-induced negative selection of thymocytes activates transcription of an NF-kappa B inhibitor.
Negative selection eliminates thymocytes bearing autoreactive T cell receptors (TCR) via an apoptotic mechanism. We have cloned an inhibitor of NF-kappa B, I kappa BNS, which is rapidly expressed upon TCR-triggered but not dexamethasone- or gamma irradiation-stimulated thymocyte death. The predicted protein contains seven ankyrin repeats and is homologous to I kappa B family members. In class I and class II MHC-restricted TCR transgenic mice, transcription of I kappa BNS is stimulated by peptides that trigger negative selection but not by those inducing positive selection (i.e., survival) or nonselecting peptides. I kappa BNS blocks transcription from NF-kappa B reporters, alters NF-kappa B electrophoretic mobility shifts, and interacts with NF-kappa B proteins in thymic nuclear lysates following TCR stimulation. Retroviral transduction of I kappa BNS in fetal thymic organ culture enhances TCR-triggered cell death consistent with its function in selection.
Fiorini
Emma
E
Laboratory of Immunobiology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Schmitz
Ingo
I
Marissen
Wilfred E
WE
Osborn
Stephanie L
SL
Touma
Maki
M
Sasada
Tetsuro
T
Reche
Pedro A
PA
Tibaldi
Elena V
EV
Hussey
Rebecca E
RE
Kruisbeek
Ada M
AM
Reinherz
Ellis L
EL
Clayton
Linda K
LK
D000595:Amino Acid Sequence; D000818:Animals; D002458:Cell Fractionation; D002469:Cell Separation; D005434:Flow Cytometry; D017930:Genes, Reporter; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology; D014158:Transcription, Genetic; D014161:Transduction, Genetic
D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D010455:Peptides; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C454819:Nfkbid protein, mouse