Melan-A/MART-1-specific CD4 T cells in melanoma patients: Identification of new epitopes specific T cells by MHC class and ex vivo visualization of II Tetramers
Melan-A/MART-1-specific CD4 T cells in melanoma patients: Identification of new epitopes specific T cells by MHC class and ex vivo visualization of II Tetramers
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DOI：
10.4049/jimmunol.177.10.6769
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发表时间：
2006-11-15
影响因子：
4.4
通讯作者：
Romero, Pedro
中科院分区：
文献类型：
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作者：
Bioley, Gilles;Jandus, Camilla;Romero, Pedro
在过去的十年中，人们做出了许多努力来从不同的肿瘤相关抗原中鉴定 MHC II 类限制性表位。 Melan-A/MART-1(26-35) 亲本表位或 Melan-A/MART-1(26-35(A27L)) 类似表位已广泛用于黑色素瘤免疫治疗中以诱导和增强 CTL 应答，但目前仅已知一种 Th 表位（Melan-A(51-73)、DRB1*0401 限制）。在这项研究中，我们描述了黑色素瘤患者的 CD4 T 细胞识别的两个新的 Melan-A/MART-1 衍生序列。这些表位可以通过 HLA-DRB1*0101 和 HLA-DRB1*0102 呈递的肽 Melan-A(27-40) 以及 HLA-DQB1*0602 和 HLA-DRB1*0301 呈递的 Melan-A(25-36) 来模拟。这些表位特异性的 CD4 T 细胞克隆识别 Melan-A/MART-1(+) 肿瘤细胞和 Melan-A/MART-1 转导的 EBV-B 细胞，并且 MHC H 类呈递途径的抑制剂会降低识别能力。这表明这些表位是由 EBV-B 细胞和黑色素瘤细胞自然加工和呈递的。此外，可以在具有可测量的 Melan-A/MART-1 特异性 CD4 T 细胞反应的患者血清中检测到 Melan-A 特异性抗体。有趣的是，即使是短的 Melan-A/MART-1(26-35(A27L)) 肽也能被 HLA-DQ6(+) 和 HLA-DR3(+) 黑色素瘤患者的 CD4 T 细胞识别。使用 Melan-A/MART-1(25-36)/DQ6 四聚体，我们可以直接离体检测黑色素瘤患者循环淋巴细胞中的 Ag 特异性 CD4 T 细胞。总之，这些结果为监测自然发生的和疫苗诱导的 Melan-A/MART-1 特异性 CD4 T 细胞反应提供了基础，从而可以对反应 T 细胞进行精确的离体表征。
Over the past decade, many efforts have been made to identify MHC class II-restricted epitopes from different tumor-associated Ags. Melan-A/MART-1(26-35) parental or Melan-A/MART-1(26-35(A27L)) analog epitopes have been widely used in melanoma immunotherapy to induce and boost CTL responses, but only one Th epitope is currently known (Melan-A(51-73), DRB1*0401 restricted). In this study, we describe two novel Melan-A/MART-1-derived sequences recognized by CD4 T cells from melanoma patients. These epitopes can be mimicked by peptides Melan-A(27-40) presented by HLA-DRB1*0101 and HLA-DRB1*0102 and Melan-A(25-36) presented by HLA-DQB1*0602 and HLA-DRB1*0301. CD4 T cell clones specific for these epitopes recognize Melan-A/MART-1(+) tumor cells and Melan-A/MART-1-transduced EBV-B cells and recognition is reduced by inhibitors of the MHC class H presentation pathway. This suggests that the epitopes are naturally processed and presented by EBV-B cells and melanoma cells. Moreover, Melan-A-specific Abs could be detected in the serum of patients with measurable CD4 T cell responses specific for Melan-A/MART-1. Interestingly, even the short Melan-A/MART-1(26-35(A27L)) peptide was recognized by CD4 T cells from HLA-DQ6(+) and HLA-DR3(+) melanoma patients. Using Melan-A/MART-1(25-36)/DQ6 tetramers, we could detect Ag-specific CD4 T cells directly ex vivo in circulating lymphocytes of a melanoma patient. Together, these results provided the basis for monitoring of naturally occurring and vaccine-induced Melan-A/MART-1-specific CD4 T cell responses, allowing precise and ex vivo characterization of responding T cells.