Generation of Cytotoxic T-Lymphocytes to a Self-Peptide/Class I Complex: A Model for Peptide-mediated Tumor Rejection

Abstract

Cytotoxic T-lymphocytes (CTL) typically recognize foreign peptides bound to class I products of the major histocompatibility complex. A function of CTL is to identify and eliminate tumor cells that bear inappropriately expressed peptide/class I complexes (i.e., mutated self-peptides or self-peptides that are expressed at abnormally high levels). The processes that result in tolerance to self-antigens can undermine the effectiveness of this system by deleting or inactivating T-cells that might potentially be reactive with tumor-associated antigens. To up-regulate the response to tumor antigens it will be useful to develop methods whereby CTL responses to specific self-peptides can be elicited without damage to normal tissue. In this report a CTL response was generated in BALB/c mice against the ubiquitous self-peptide p2Ca (LSPFPFDL), which binds to L^d and is derived from the mitochondrial enzyme α-ketoglutarate dehydrogenase. CTL derived in vitro recognize specifically the p2Ca/L^d complex and use Vβ8 regions predominantly. The cultured cells lysed target cells with lower levels of p2Ca than the levels used for induction. This result suggests that it may be possible to use peptides at high concentrations to elicit CTL that react with endogenous levels of a peptide/class I complex. The in vivo potential of the response was demonstrated by the observation that BALB/c mice, coinjected with a syngeneic BALB/c myeloma and exogenous p2Ca, are able to reject the tumor. The p2Ca/L^d system may thus provide a model for evaluating the parameters for effective immunotherapy with tumor-associated peptides.