Lack of activation induced cell death in human T blasts despite CD95L up-regulation: protection from apoptosis by MEK signalling

The generation of effective immunity requires that antigen-specific T cells are activated, clonally expanded and ultimately eliminated by apoptosis. T he involvement of CD95-mediated apoptosis in T-cell elimination is well est ablished, but the conditions which regulate the death pathway under normal circumstances are still emerging. Using superantigen-activated human T cell s, we found that whilst T-cell receptor (TCR) signalling triggered up-regul ation of CD95 ligand (CD95L), the majority of T cells were resistant to apo ptosis induction, despite co-expressing high levels of CD95. Resistance was maintained following direct antibody-mediated cross-linking of CD95 and wa s not confined to early time periods following activation. Our data implica te TCR-derived signals in protection from apoptosis and reveal a role for t he mitogen-activated protein (MAP) kinase pathway by use of a MAP kinase ki nase (MEK) inhibitor. Collectively these data demonstrate that resistance t o activation-induced cell death in human T cells is prolonged rather than t ransient, is not attributable to a lack of CD95L up-regulation and is due, at least in part, to signalling via the MEK pathway.