Generation of human T-cell responses to an HLA-A2.1-restricted peptide epitope derived from alpha-fetoprotein.
Alpha-fetoprotein (AFP) is often derepressed in human hepatocellular carcinoma. Peptide fragments of AFP presented in the context of major histocompatibility molecules could serve as potential recognition targets by CD8 T cells, provided these lymphocytes were not clonally deleted in ontogeny. We therefore wished to determine whether the human T-cell repertoire could recognize AFP-derived peptide epitopes in the context of a common class I allele, HLA-A2.1. Dendritic cells genetically engineered to express AFP were capable of generating AFP-specific T-cell responses in autologous human lymphocyte cultures and in HLA-A2.1/Kb transgenic mice. These T cells recognize a 9-mer peptide derived from the AFP protein hAFP(542-550) (GVALQTMKQ). Identified as a potential A2.1-restricted peptide epitope from a computer analysis of the AFP sequence, hAFP(542-550) proved to have low binding affinity to A2.1, but slow off-kinetics. AFP-specific CTL- and IFN-gamma-producing cells recognize hAFP(542-550)-pulsed targets. Conversely, hAFP(542-550) peptide-generated T cells from both human lymphocyte cultures and A2.1/Kb transgenic mice recognized AFP-transfected targets in both cytotoxicity assays and cytokine release assays. These lines of evidence clearly demonstrate that AFP-reactive clones have not been deleted from the human T-cell repertoire and identify one immunodominant A2.1-restricted epitope. These findings also clearly establish AFP as a potential target for T-cell-based immunotherapy.
Butterfield
L H
LH
Division of Surgical Oncology, University of California Los Angeles Medical Center, University of California Los Angeles, 90095-1782, USA.
Koh
A
A
Meng
W
W
Vollmer
C M
CM
Ribas
A
A
Dissette
V
V
Lee
E
E
Glaspy
J A
JA
McBride
W H
WH
Economou
J S
JS
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000494:pharmacology*; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000276:immunology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014162:Transfection; D000509:alpha-Fetoproteins / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology
D000939:Epitopes; D015789:HLA-A2 Antigen; D011994:Recombinant Proteins; D000509:alpha-Fetoproteins