Partial activation of CD8⁺ T cells by a self-derived peptide

Abstract

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 by 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 routes¹⁶, 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.