FAS (CD95) PARTICIPATES IN PERIPHERAL T-CELL DELETION AND ASSOCIATED APOPTOSIS IN-VIVO

Following exposure to some types of antigen (superantigens), responsiv e T cells expand and then decline in numbers, a phenomenon that has be en called 'peripheral deletion'. This process may play a role in limit ing autoimmune reactions and in the maintenance of immune homeostasis, Here we describe experiments on peripheral deletion in mice carrying the lpr/lpr defect, which has been shown to be due to defective produc tion of the CD95/Fas molecule. Young lpr/lpr mice with no apparent imm unologic abnormalities display a defect in bacterial superantigen-indu ced peripheral deletion. Apoptotic death of the expanded T cell popula tion associated with such peripheral deletion in normal animals is dra matically reduced in the mutant mice, Further, the levels of Fas on re sponding cells in normal mice increases and decreases together with in creases and decreases in cell numbers, suggesting that cells with the highest levels of Fas are preferentially deleted, These observations a re consistent with the known ability of CD95 to transduce a signal lea ding to apoptosis, and they implicate this signal transduction pathway in peripheral deletion, In contrast, bacterial superantigen-induced d eletion of thymocytes appears to be fully functional in these mice, an d thus Fas/APO-1 does not appear to be required for this process, furt her, antibody ligation of the TCR on activated T cells from normal or young lpr/lpr mice can induce apoptosis and therefore under some circu mstances this phenomenon is not dependent upon CD95/Fas, Thus, to avoi d autoreactivity and ensure immune homeostasis, several different apop totic mechanisms exist in peripheral T lymphocytes, only some of which involve Fas, Defects in one or more of these mechanisms may have prof ound deleterious consequences.