Activated human γδ T cells induce peptide-specific CD8+ T-cell responses to tumor-associated self-antigens
Activated human γδ T cells induce peptide-specific CD8+ T-cell responses to tumor-associated self-antigens
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DOI：
10.1007/s00262-011-1111-6
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发表时间：
2012-03-01
影响因子：
5.8
通讯作者：
Rossig, Claudia
中科院分区：
文献类型：
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作者：
Altvater, Bianca;Pscherer, Sibylle;Rossig, Claudia
肿瘤的特异性细胞免疫治疗需要高效地产生和扩增识别肿瘤相关自身抗原的细胞毒性T淋巴细胞(CTL)。在这里，我们研究了人Gamma Delta T细胞诱导CD8+T细胞增殖的能力，CD8+T细胞针对来自弱免疫原性肿瘤相关自身抗原PRAME和STEAP1的多肽。用氨基二膦酸盐刺激的人外周血源γ-Delta T细胞(V-Gamma 9+V Delta 2+)负载了PRAME的HLA-A*02限制性表位，与自体外周血CD8+T细胞共孵育，刺激了多肽特异性细胞溶解效应记忆T细胞的扩增。此外，负载多肽的Gamma Delta T细胞能有效地激发抗原初始的CD45RA+CD8+T细胞对抗PRAME多肽。与成熟树突状细胞的直接比较显示，在诱导初始T细胞反应和多肽特异性T细胞激活和扩增方面，伽马增量T细胞和树突状细胞的效力相同。T-APC的抗原提呈不能克服多肽特异性T细胞与表达全长抗原的靶细胞相互作用的有限能力。重要的是，与Gamma Delta T细胞共培养时，具有调节性表型(CD4+CD25hiFoxP3+)的T细胞低于DC。综上所述，双膦酸盐激活的伽马增量T细胞允许产生针对弱免疫原性肿瘤相关表位的CTL。利用这一策略进行有效的癌症免疫治疗需要增强CTL反应的亲和力的策略，以允许有效地靶向癌症。
Specific cellular immunotherapy of cancer requires efficient generation and expansion of cytotoxic T lymphocytes (CTLs) that recognize tumor-associated self-antigens. Here, we investigated the capacity of human gamma delta T cells to induce expansion of CD8+ T cells specific for peptides derived from the weakly immunogenic tumor-associated self-antigens PRAME and STEAP1. Coincubation of aminobisphosphonate-stimulated human peripheral blood-derived gamma delta T cells (V gamma 9+V delta 2+), loaded with HLA-A*02-restricted epitopes of PRAME, with autologous peripheral blood CD8+ T cells stimulated the expansion of peptide-specific cytolytic effector memory T cells. Moreover, peptide-loaded gamma delta T cells efficiently primed antigen-naive CD45RA+ CD8+ T cells against PRAME peptides. Direct comparisons with mature DCs revealed equal potency of gamma delta T cells and DCs in inducing primary T-cell responses and peptide-specific T-cell activation and expansion. Antigen presentation by gamma delta T-APCs was not able to overcome the limited capacity of peptide-specific T cells to interact with targets expressing full-length antigen. Importantly, T cells with regulatory phenotype (CD4+CD25hiFoxP3+) were lower in cocultures with gamma delta T cells compared to DCs. In summary, bisphosphonate-activated gamma delta T cells permit generation of CTLs specific for weakly immunogenic tumor-associated epitopes. Exploiting this strategy for effective immunotherapy of cancer requires strategies that enhance the avidity of CTL responses to allow for efficient targeting of cancer.