Evidence that HLA class II-restricted human CD4+ T cells specific to p53 self peptides respond to p53 proteins of both wild and mutant forms.
By stimulating peripheral blood mononuclear cells of four healthy donors with a mixture of overlapping peptides representing the core domain of p53, we established two CD4+ alphabeta T cell clones and four lines that recognized wild-type and mutant p53 proteins as well as p53 self peptides in an HLA class II-restricted fashion. Two T cell lines established from two unrelated donors reacted to the p53 peptide (p)153-166 and p108-122, respectively, in the context of DP5 molecules. Two T cell clones established from two other unrelated donors were specific for p193-204 in the context of DRB1*1401 and for p153-165 in the context of DP5, respectively. These two T cell clones responded almost equally to both wild-type and four mutant recombinant p53 proteins. The proliferative responses of these T cell clones to p53 recombinant proteins were augmented by heat denaturing, thereby suggesting that altered conformation of the protein facilitates proteolytic processing to produce antigenic peptides. The DRB1*1401-restricted T cell clone specific for p193-204 killed a B lymphoblastoid cell line homozygous for HLA-DRB1*1401 when the cell line was pre-pulsed with p53 protein as well as peptide. These results indicate that CD4+ T cells reactive to p53 do exist in healthy individuals and the epitopes are probably ignored by the immune system under physiological conditions. It is suggested that such epitopes stimulate T cells to induce anti-p53 antibody production in cancer patients as previously reported by others. The possible involvement of p53-reactive T cells in anti-tumor immunity is discussed.
Fujita
H
H
Department of Neuroscience and Immunology, Kumamoto University Graduate School of Medical Sciences, Japan.
Senju
S
S
Yokomizo
H
H
Saya
H
H
Ogawa
M
M
Matsushita
S
S
Nishimura
Y
Y
D000328:Adult; D000595:Amino Acid Sequence; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D016158:Genes, p53; D006684:HLA-DR Antigens / Q000276:immunology*; D059811:HLA-DRB1 Chains; D006801:Humans; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*; D011487:Protein Conformation; D011489:Protein Denaturation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000276:immunology*
D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D008222:Lymphokines; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53