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 indu ced through non-antigen-specific receptors such as Fas (CD95/APO-1) or TNFR. We define a selective TCR that controls apoptosis by Fas or TNF R 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 no t 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 periphera l T cell tolerance.