RESUMO
Cytotoxic T-lymphocyte (CTL) responses directed to different human immunodeficiency virus (HIV) epitopes vary in their protective efficacy. In particular, HIV-infected cells are much more sensitive to lysis by anti-Gag/p17(77-85)/HLA-A2 than to that by anti-polymerase/RT(476-484)/HLA-A2 CTL, because of a higher density of p17(77-85) complexes. This report describes multiple processing steps favoring the generation of p17(77-85) complexes: (i) the exact COOH-terminal cleavage of epitopes by cellular proteases occurred faster and more frequently for p17(77-85) than for RT(476-484), and (ii) the binding efficiency of the transporter associated with antigen processing was greater for p17(77-85) precursors than for the RT(476-484) epitope. Surprisingly, these peptides, which differed markedly in their antigenicity, displayed qualitatively and quantitatively similar immunogenicity, suggesting differences in the mechanisms governing these phenomena. Here, we discuss the mechanisms responsible for such differences.
Assuntos
Apresentação de Antígeno/imunologia , Cisteína Endopeptidases , Epitopos de Linfócito T/imunologia , Produtos do Gene gag/imunologia , Antígenos HIV/imunologia , Infecções por HIV/imunologia , Transcriptase Reversa do HIV/imunologia , HIV-1/imunologia , Antígeno HLA-A2/imunologia , Epitopos Imunodominantes/imunologia , Complexos Multienzimáticos , Linfócitos T Citotóxicos/imunologia , Proteínas Virais , Sequência de Aminoácidos , Transporte Biológico , Endopeptidases/metabolismo , Epitopos de Linfócito T/metabolismo , Produtos do Gene gag/metabolismo , Antígenos HIV/metabolismo , Transcriptase Reversa do HIV/metabolismo , Humanos , Epitopos Imunodominantes/metabolismo , Complexo Principal de Histocompatibilidade , Dados de Sequência Molecular , Complexo de Endopeptidases do Proteassoma , Precursores de Proteínas/metabolismo , Proteínas/metabolismo , Produtos do Gene gag do Vírus da Imunodeficiência HumanaRESUMO
In many types of cancer, p53 frequently accumulates in tumor cells and anti-p53 antibodies can be detected. However, only four CD8(+) T-cell epitopes from p53 have been identified in humans so far. To further analyze the development of a T-cell response against p53, peptides having binding motifs specific for HLA-A1, -A2, -A3, -A24, -B7, -B35, -B44, and -B51 molecules have been defined. The HLA-binding capacity of those peptides was tested, and the stability of formed complexes was defined. Thirteen peptides that bound to HLA-A24 and -B44 molecules are presented. The positive peptides were then used to detect the anti-p53 response of CD8(+) T lymphocytes from patients with bladder cancer. Six peptides, presented by HLA-A2, -B51, or -A24, were able to stimulate T cells from two patients (among 16) with tumor cells that strongly accumulated p53. On the contrary, p53 peptides systematically failed to stimulate T cells from healthy donors or patients with low or undetectable levels of p53 in their tumor cells. These results have led to the identification of four new potential T CD8(+) epitopes from p53: 194-203 associating with HLA-B51 and 204-212, 211-218, and 235-243 associating with HLA-A24.
