ALLOREACTIVE CYTOTOXIC T-LYMPHOCYTES GENERATED IN THE PRESENCE OF VIRAL-DERIVED PEPTIDES SHOW EXQUISITE PEPTIDE AND MHC SPECIFICITY

The nature of alloreactivity to MHC molecules has been enigmatic, prim arily because of the observation that allogeneic responses are conside rably stronger than syngeneic responses. To better determine the speci ficity potential of allogeneic responses, we have generated alloreacti ve CTL specific for exogenous, viral-derived peptide ligands. This app roach allowed us to critically evaluate both the peptide- and MHC-spec ificity of these alloreactive T cells. Exploiting the accessibility of the H-2L(d) class I molecule for exogenous peptide ligands, alloreact ive CTL were generated that are specific for either murine cytomegalov irus (MCMV) or lymphocytic choriomeningitis virus (LCMV) peptides boun d by L(d) alloantigens. Peptide specificity was initially observed in bulk cultures of alloreactive CTL only when tested on peptide-sensitiz ed T2.L(d) target cells that have defective presentation of endogenous peptides. Subsequent cloning of bulk alloreactive CTL lines generated to MCMV yielded CTL clones that had exquisitely specific MCMV peptide recognition requirement. All of the MCMV/L(d) alloreactive CTL clones were also exquisitely MHC-specific in that none of the CTL clones lys ed targets expressing MCMV/L(q) complexes, even though L(q) differs fr om L(d) by only six amino acid residues and L(q) also binds the MCMV p eptide. This observation clearly demonstrates that alloreactive CTL ar e capable of the same degree of specificity for target cell recognitio n as are syngeneic CTL in MHC-restricted responses.