T cells are normally activated when the peptide for which they are specific is presented to them in the context of the appropriate major histocompatibility complex (MHC) (class I and Class II for CD8+ and CD4+ T cells, respectively). An increasing body of evidence indicates that structural homologues of the immunogenic peptide can partially activate or antagonize CD4+ T cells. CD8+ T cells may also be partially antagonized by such peptides, and self-derived peptides of this type may play a role in CD8+ T cell selection in the thymus. Activated CD8+ T cells lyse their targets by perforin-dependent granule exocytosis and by inducing apoptosis mediated by CD95 (also known as Fas or APO1) with its ligand (CD95L). Here we show that a clone of Kd-restricted CD8+ T cells specific for influenza haemagglutinin, which can also be activated in a crossreactive manner by a peptide derived from a myeloma tumour immunoglobulin heavy-chain variable region (IgVH) to kill by both routes, kills only by the CD95-CD95L pathway when stimulated by the corresponding germline IgVH peptide. As this germline IgVH peptide differs from the tumour peptide only at a single position buried in the MHC-binding groove, this indicates that CD95-CD95L-mediated killing can be triggered independently of the perforin-mediated pathway, and can be selectively affected by changes in MHC conformation.