Identification of a human cyclin D1-derived peptide that induces human cytotoxic CD4 T cells.
Identification of a human cyclin D1-derived peptide that induces human cytotoxic CD4 T cells.
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DOI：
10.1371/journal.pone.0006730
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发表时间：
2009-08-25
期刊：
影响因子：
3.7
通讯作者：
Scheinberg DA
中科院分区：
文献类型：
--
作者：
Dao T;Korontsvit T;Zakhaleva V;Haro K;Packin J;Scheinberg DA
Cyclin D1在多种人类肿瘤中过表达，因此可能是一种潜在的致癌靶抗原。然而，只有有限数量的T细胞表位被表征。我们旨在鉴定包括CD4和CD8 T细胞表位的人类细胞周期蛋白d1衍生肽，并测试这些多表位肽是否可以产生改善的细胞毒性CD8 T细胞反应以及细胞毒性CD4 T细胞。五HLA-DR。通过计算机算法预测含有多个重叠CD4表位和hla - a0201限制性CD8 T细胞表位的b1结合肽。通过体外刺激健康供体的T细胞来评估合成肽的免疫原性，并通过IFN-γ ELISPOT和51Chromium释放法检测表位识别。HLA-DR。设计为“DR-1”的B1肽，其中嵌入hla - a0201结合表位（D1-1），在IFN-γ ELISPOT检测中诱导CD3 T细胞对DR-1和D1-1肽的反应。这表明从DR-1序列中加工了较短的D1-1表位。然而，只有dr -1刺激的CD4或CD3 T细胞对肽脉冲的自体dc和表达高水平cyclin D1的癌细胞系具有细胞毒性。HLA-DR单克隆抗体可消除CD3和CD4 T细胞的表位特异性应答，显示ii类介导的杀伤。我们的研究提示了CD4 T细胞在抗肿瘤免疫中的可能作用，作为表达HLA-DR的癌症的细胞毒性效应物，并为设计包含CD4表位的肽疫苗提供了理论依据。
Cyclin D1 is over-expressed in various human tumors and therefore can be a potential oncogenic target antigen. However, only a limited number of T cell epitopes has been characterized. We aimed at identifying human cyclin D1-derived peptides that include both CD4 and CD8 T cell epitopes and to test if such multi-epitope peptides could yield improved cytotoxic CD8 T cell responses as well as cytotoxic CD4 T cells. Five HLA-DR.B1-binding peptides containing multiple overlapping CD4 epitopes and HLA-A0201-restricted CD8 T cell epitopes were predicted by computer algorithms. Immunogenicity of the synthetic peptides was assessed by stimulating T cells from healthy donors in vitro and the epitope recognition was measured by IFN-γ ELISPOT and 51Chromium release assays. A HLA-DR.B1 peptide, designed “DR-1”, in which a HLA-A0201-binding epitopes (D1-1) was imbedded, induced CD3 T cell responses against both DR-1 and D1-1 peptides in IFN-γ ELISPOT assay. This suggested processing of the shorter D1-1 epitope from the DR-1 sequence. However, only DR-1-stimulated CD4 or CD3 T cells possessed cytotoxicity against peptide-pulsed autologous DCs and a cancer cell line, that expresses a high level of cyclin D1. Monoclonal antibody to HLA-DR abrogated the epitope-specific responses of both CD3 and CD4 T cells, demonstrating class II-mediated killing. Our studies suggest a possible role of CD4 T cells in anti-tumor immunity as cytotoxic effectors against HLA-DR expressing cancers and provide a rationale for designing peptide vaccines that include CD4 epitopes.
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DOI：
10.1084/jem.188.12.2357
发表时间：
1998-12-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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影响因子：
158.5
作者：
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影响因子：
4.4
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通讯作者：
van der Burg, Sjoerd H.
DOI：
10.1084/jem.20050162
发表时间：
2005-10-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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通讯作者：
Johnson DC
影响因子：
20.3
作者：
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通讯作者：
Gnjatic, Sacha