Apoptosis in T cells that have penetrated into the central nervous system (CNS) may be important for the physiological control of T cells with potentially dangerous reactivities to CNS antigens; such control may be dysfunctional in animals suffering from experimental autoimmune encephalomyelitis (EAE). In this study we examined the expression of Fas and FasL genes both in myelin basic protein (MBP)-reactive T cells and in glial cells and the susceptibility of these cells to death induced by Fas/FasL interaction. Both Fas and FasL gene expression is detectable in glial cells and MBP-reactive T cells. Cell death is not unidirectional: when T cells interact with glial cells death can be induced in the former or in the latter population. The ability to induce death of Fas-expressing cells varies greatly among different lines of MBP-reactive T cells, as does resistance to death induction by cells expressing FasL. Moreover, the ability of T cells both to deliver and to resist death signals is a function of their activation status: T cells freshly activated transmit a stronger apoptotic signal to Fas-positive target cells and are also more resistant to FasL-induced suicide. Soluble form of FasL provides a convenient titratable means of delivering death signals via Fas. However, comparison of the susceptibility of different targets to soluble FasL and to FasL expressed on the surface of a transfected glial line revealed differences, suggesting that signals arising from Fas/FasL interaction may be modulated by additional cell- surface molecules.