GENERATION OF CYTOTOXIC T-LYMPHOCYTES TO A SELF-PEPTIDE CLASS-I COMPLEX - A MODEL FOR PEPTIDE-MEDIATED TUMOR REJECTION

Cytotoxic T-lymphocytes (CTL) typically recognize foreign peptides bou nd to class I products of the major histocompatibility complex. A func tion of CTL is to identify and eliminate tumor cells that bear inappro priately expressed peptide/class I complexes (i.e., mutated self-pepti des or self-peptides that are expressed at abnormally high levels). Th e processes that result in tolerance to self-antigens can undermine th e effectiveness of this system by deleting or inactivating T-cells tha t might potentially be reactive with tumor-associated antigens. To up- regulate the response to tumor antigens it will be useful to develop m ethods whereby CTL responses to specific self-peptides can be elicited without damage to normal tissue. In this report a CTL response was ge nerated in BALB/c mice against the ubiquitous self-peptide p2Ca (LSPFP FDL), which binds to L(d) and is derived from the mitochondrial enzyme alpha-ketoglutarate dehydrogenase. genase. CTL derived in vitro recog nize specifically the p2Ca/L(d) complex and use Vbeta8 regions predomi nantly. The cultured cells lysed target cells with lower levels of p2C a 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 viv o potential of the response was demonstrated by the observation that B ALB/c mice, coinjected with a syngeneic BALB/c myeloma and exogenous p 2Ca, are able to reject the tumor. The p2Ca/L(d) system may thus provi de a model for evaluating the parameters for effective immunotherapy w ith tumor-associated peptides.