Up-regulation of c-FLIPshort and reduction of activation-induced cell death in CD28-co-stimulated human T cells

Efficient activation of antigen-specific T cells requires co-stimulatory si gnals provided e.g. by CD28. Re-exposure to antigen and CD28 cc-stimulation reduces activation-induced cell death (AICD) and increases the number of T cells performing effector functions. AICD is mediated predominantly by CD9 5 (APO-1/Fas) and its cognate ligand (CD95L). In an in vitro model system, using human peripheral activated T cells, we demonstrate here that costimul ation prevents CD95L expression. Moreover, we show that co-stimulation redu ces the activity of the CD95 death-inducing signaling complex and procaspas e-8 activation. In parallel, co-stimulation strongly increases expression o f the short form of the FLICE-inhibitory protein c-FLIPshort and of Bcl-x(L ). These data provide important new insight into the molecular mechanisms o f apoptosis resistance in co-stimulated T cells.