Peptide-pulsed dendritic cells induce tumoricidal cytotoxic T lymphocytes from healthy donors against stably HLA-A*0201-binding peptides from the Melan-A/MART-1 self antigen
Peptide-pulsed dendritic cells induce tumoricidal cytotoxic T lymphocytes from healthy donors against stably HLA-A*0201-binding peptides from the Melan-A/MART-1 self antigen
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DOI：
10.1002/eji.1830260803
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发表时间：
1996-08-01
影响因子：
5.4
通讯作者：
Schrier, PI
中科院分区：
文献类型：
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作者：
vanElsas, A;vanderBurg, SH;Schrier, PI
筛选黑色素瘤抗原Melan-A/MART-1是否存在潜在的HLA-A*0201结合的细胞毒性T淋巴细胞（CTL）表位。免疫显性非分子表位AAGIGILTV与T2结合较弱，但与HLA-A*0201结合的半衰期明显高于十分子EAAGIGILTV。除了免疫显性CTL表位外，我们还描述了两种肽，GILTVILGV和ALMDKSLHV，它们与HLA-A*0201稳定结合。用这些肽脉冲培养的自体树突状细胞，从外周血淋巴细胞诱导CTL细胞系，这些淋巴细胞与HLA-A2(+), Melan-A/MART-1（+）黑色素瘤细胞表现出反应性。单用非amer表位可以诱导CTL对免疫优势表位的反应性，但不能用decamer变体。由（EAAGIGILTV + AAGIGILTV）诱导的CTL克隆可识别适当的黑色素瘤细胞和正常的黑色素细胞。在进一步表征这些CTL克隆之一后，发现它具有惊人的高亲和力，考虑到它是针对自身抗原的。本研究表明，免疫原性肽可以根据肽/ HLA结合的稳定性（半衰期）来选择。此外，体外培养的DC可以有效地诱导CTL反应，并且其中一些CTL能够识别内源性加工抗原。
The melanoma antigen Melan-A/MART-1 was screened for the presence of potential HLA-A*0201-binding cytotoxic T lymphocytes (CTL) epitopes. The immunodominant nonamer epitope AAGIGILTV demonstrated weak binding to T2 but a significant half-life of binding to HLA-A*0201 in contrast to the decamer EAAGIGILTV. In addition to the immunodominant CTL epitope, we describe two peptides, GILTVILGV and ALMDKSLHV, that display stable binding to HLA-A*0201. Using cultured autologous dendritic cells pulsed with these peptides, CTL lines were induced from peripheral blood lymphocytes that displayed reactivity with HLA-A2(+), Melan-A/MART-1(+) melanoma cells. CTL reactivity against the immunodominant epitope could be induced with the nonamer epitope alone, but not with the decamer variant. CTL clones generated from an (EAAGIGILTV + AAGIGILTV)-induced CTL line recognize the appropriate melanoma cells and normal melanocytes. Upon further characterization of one of these CTL clones, it was found to be of surprisingly high affinity considering that it is directed against a self antigen. This study demonstrates that immunogenic peptides can be selected based on stability (half-life) of peptide/ HLA binding. In addition, cultured DC were found to efficiently induce CTL responses in vitro against such selected peptides, and some of these CTL were capable of recognizing endogenously processed antigen.