The roles of costimulation and Fas in T cell apoptosis and peripheral tolerance.

Using cells from TCR transgenic mice that do or do not express Fas, we show that there are two mechanistically distinct forms of apoptosis in CD4+ T cells. Naive T cells undergo apoptosis if cultured in the absence of antigen or costimulation. This form of programmed cell death (PCD) is not dependent on Fas, and is prevented by CD28-mediated signals, which lead to the secretion of growth factors and the expression of survival genes, such as bcl-xL. Recently activated T cells undergo apoptotic death upon repeated stimulation. This activation-induced cell death (AICD) is mediated by Fas, but is independent of costimulation and is not prevented by IL-2 or bcl-xL. Finally, we show that peripheral tolerance may be induced in vivo independent of Fas-mediated cell death.