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 immunotherapy of hepatocellular carcinoma (HCC). AFP(542-550) (GVALQTMKQ) is one of several HLA-A2.1-restricted immunodominant AFP peptides that consistently generate AFP-specific T cell responses in human T cell cultures and in HLA-A2.1/K(b) transgenic (A2.1 tg) mice. We performed a fine specificity analysis of this nonamer to determine which amino acid side chains were critical for T cell priming and recognition. Using peptide-pulsed dendritic cells (DC) as an immunization strategy, we characterized the effects of AFP(542-550) amino acid substitutions on priming and recognition in A2.1 tg mice. Replacing the glutamine at anchor position 9 with a leucine enhanced MHC binding and AFP-specific T cell responses. Substitution of leucine at non-anchor position 4 with an alanine did not alter binding but greatly diminished T cell recognition. Computer-generated three-dimensional models provided the structural rationale for these observed effects in MHC binding and T cell responses resulted from the modifications in the AFP(542-550) sequence.
Meng
W S
WS
Room 54-140 CHS, Division of Surgical Oncology, UCLA School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, 90095-1782, Los Angeles, CA, USA.
Butterfield
L H
LH
Ribas
A
A
Heller
J B
JB
Dissette
V B
VB
Glaspy
J A
JA
McBride
W H
WH
Economou
J S
JS
D000596:Amino Acids / Q000276:immunology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000628:therapy; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D007167:Immunotherapy; D008113:Liver Neoplasms / Q000276:immunology / Q000628:therapy; D008213:Lymphocyte Activation; D051379:Mice; D008958:Models, Molecular; D009842:Oligopeptides / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011948:Receptors, Antigen, T-Cell; D013601:T-Lymphocytes / Q000276:immunology*; D000509:alpha-Fetoproteins / Q000276:immunology*
D000596:Amino Acids; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D009842:Oligopeptides; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D000509:alpha-Fetoproteins