HUMAN-LEUKOCYTE ANTIGEN PHENOTYPE IMPOSES COMPLEX CONSTRAINTS ON THE ANTIGEN-SPECIFIC CYTOTOXIC T-LYMPHOCYTE REPERTOIRE

The memory response to the immunodominant Epstein-Barr virus (EBV) epi tope FLRGRAYGL, which associates with HLA B8, is exceptionally restric ted, being dominated by cytotoxic T lymphocytes (CTL) with a single, p ublic T cell receptor (TCR). CTL clones that express this receptor for tuitously cross-react with the alloantigen HLA B44. However, of the tw o major subtypes of this HLA, B4402 and B*4403, that differ by a sing le amino acid, only the former is recognized by these mature CTL clone s. Individuals heterozygous for HLA EX and B4402 use alternative TCR for the EBV determinant since the dominant TCR is potentially self-rea ctive. We now demonstrate that this clonotype is also essentially abse nt from the repertoire of CTL directed against the viral epitope in se ven from seven unrelated individuals heterozygous for HLA B8 and B440 (3) under bar. Thus immune tolerance of these CTL recognizing HLA B4 402 is associated with expression of either B4402 or B*4403. This sug gests that tolerance in the human T cell compartment requires a lower threshold of recognition than for effector function, thus providing a buffer zone minimizing the risk of autoimmunity. These data also illus trate the potential for non-restricting HLA molecules to bias dramatic ally the T cell repertoire used for specific immune responses. Such in fluences may be the basis of the ''protective'' effects of certain HLA alleles in susceptibility to autoimmune disorders.