Fine specificity analysis of an HLA-A2.1-restricted immunodominant T cell epitope derived from human alpha-fetoprotein

Human alpha -fetoprotein (AFP) is a potentially important target for the im munotherapy of hepatocellular carcinoma (HCC). AFP(542-550) (GVALQTMKQ) is one of several HLA-A2.1-restricted immunodominant AFP peptides that consist ently generate AFP-specific T cell responses in human T cell cultures and i n HLA-A2.1/K-b transgenic (A2.1 tg) mice. We performed a fine specificity a nalysis of this nonamer to determine which amino acid side chains were crit ical for T cell priming and recognition. Using peptide-pulsed dendritic cel ls (DC) as an immunization strategy, we characterized the effects of AFP(54 2-550) amino acid substitutions on priming and recognition in A2.1 tg mice. Replacing the glutamine at anchor position 9 with a leucine enhanced MHC b inding and AFP-specific T cell responses. Substitution of leucine at non-an chor position 4 with an alanine did not alter binding but greatly diminishe d T cell recognition. Computer-generated three-dimensional models provided the structural rationale for these observed effects in MHC binding and T ce ll responses resulted from the modifications in the AFP(542-550) sequence. (C) 2001 Elsevier Science Ltd. All rights reserved.