DISSOCIATION OF T-CELL ANERGY FROM APOPTOSIS BY BLOCKADE OF FAS APO-1(CD95) SIGNALING/

Induction of anergy and deletion due to apoptosis are two of the mecha nisms involved in peripheral tolerance. To clarify the relationship be tween these two phenomena we have used an in vitro system of T cell Ag presentation. The recognition of Ag displayed by MHC class II-express ing T cells (T-APC) induces partial signals in Ag-specific T cell clon es. This leads to a blunted intracellular calcium flux, and the T cell s become unable to proliferate in response to further challenge with p rofessional APC. These T cells are unable to produce IL-2, but retain the ability to release IL-4. In the present study, we report that for some T cell clones, the predominant outcome of Ag recognition on T cel ls is cell death. For susceptible T cell clones, the number of cells t hat die is proportional to the peptide concentration. This cell death resulted from Fas/Apo-1 (CD95)/Fas-ligand interactions between the T c ells, in that Fas ligand expression was detected following overnight c ulture of T cells with T-APC and neutralizing anti-CD95 Ab protected f rom death. Most notably, following anti-CD95-mediated protection from apoptosis, the rescued T cells remained unable to respond to rechallen ge with Ag-pulsed, professional APC. These data suggest that anergy an d apoptosis can be separated as consequences of partial T cell signali ng.