Differential TCR signaling regulates apoptosis and immunopathology during antigen responses in vivo.
Clonal selection theories postulate that lymphocyte fate is regulated by antigen receptor specificity. However, lymphocyte apoptosis is induced through nonantigen-specific receptors such as Fas (CD95/APO-1) or TNFR. We define a selective TCR that controls apoptosis by Fas or TNFR stimulation. Variant ligands can deliver this "competence to die" signal without the full TCR signals necessary for cytokine synthesis. These partial agonists regulate T cell deletion in vivo even when Fas or TNF is provided by T cells of unrelated specificity, but they do not cause the liver necrosis that is associated with T cell elimination by the full agonist. Thus, selective signaling ligands regulate T cell deletion and immune damage in vivo and may be important for peripheral T cell tolerance.
Molecular Development of the Immune System Section, Laboratory of Immunology National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, Maryland 20892-1892, USA.
B
B
Combadière
C
C
Reis e Sousa
C
C
Trageser
L X
LX
Zheng
C R
CR
Kim
M J
MJ
Lenardo
D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D016923:Cell Death; D002478:Cells, Cultured; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D053222:Fas Ligand Protein; D005260:Female; D007111:Immunity, Cellular / Q000276:immunology*; D008099:Liver / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D009336:Necrosis; D010455:Peptides / Q000819:agonists / Q000276:immunology / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D000941:Antigens; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha