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(1-3). CD8(+) T cells may also be partially antagonized by such peptides(4,5), and self-derived peptides of this type may play a role in CD8(+) T cell selection in the thymus(6-8). Activated CD8(+) T cells lyse their targets by perforin-dependent granule exocytosis(9,10) and by inducing apoptosis mediated bs CD95 (also known as Fas or APO1) with its ligand (CD95L)(11-15). Here we show that a clone of K-d-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(16), 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 be triggered independently of the perforin-mediated pathway, and can be selectively affected by changes in MHC conformation.