Activated human gammadelta T cells as stimulators of specific CD8+ T-cell responses to subdominant Epstein Barr virus epitopes: potential for immunotherapy of cancer.
Activated human gammadelta T cells as stimulators of specific CD8+ T-cell responses to subdominant Epstein Barr virus epitopes: potential for immunotherapy of cancer.
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DOI：
10.1097/cji.0b013e31819b7c30
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发表时间：
2009-04
期刊：
影响因子：
--
通讯作者：
Rossig C
中科院分区：
文献类型：
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作者：
Landmeier S;Altvater B;Pscherer S;Juergens H;Varnholt L;Hansmeier A;Bollard CM;Moosmann A;Bisping G;Rossig C
目前的癌症疫苗的功效受到功能异质性和专业抗原呈递细胞（APC）的较差可用性和扩增的限制。除了其有效的先天效应特性之外，γδ T细胞还被认为参与适应性免疫应答的启动和维持。在此，我们研究了人γδ T细胞诱导病毒特异性T细胞扩增至Epstein巴尔病毒（EBV）抗原的能力。氨基二膦酸盐刺激的人外周血来源的γδ T细胞（Vγ9+Vδ2+）获得了APC和效应记忆T细胞的双重表型特征。用高刺激性EBV裂解周期抗原BZLF-1或肿瘤相关潜伏性EBV抗原LMP 2a的HLA限制性表位脉冲的活化γδ T细胞与自体外周血淋巴细胞共孵育诱导肽特异性、全功能性CD 3 + CD 8+细胞溶解效应记忆T细胞的选择性扩增。此外，γδ T-APC有效地加工和呈递内源性抗原，如通过LMP 2a基因转导的γδ T细胞诱导T细胞扩增的能力所证明的，所述扩增对各种LMP 2a肽具有广泛的特异性。自体γδ T细胞诱导LMP 2a特异性自体CTL的能力在两名霍奇金淋巴瘤患者中得到证实。总之，二膦酸盐活化的人γδ T细胞刺激特异于亚显性和显性病毒表位的细胞毒性效应T细胞的扩增，因此显示出作为用于病毒和恶性疾病免疫治疗的有效APC的新来源的前景。
The efficacy of current cancer vaccines is limited by the functional heterogeneity and poor availability and expansion of professional antigen-presenting cells (APCs). Besides their potent innate effector properties, γδ T cells have been suggested to be involved in the initiation and maintenance of adaptive immune responses. Here, we investigated the capacity of human γδ T cells to induce expansion of virus-specific T cells to Epstein Barr virus (EBV) antigens. Aminobisphosphonate-stimulated human peripheral blood-derived γδ T cells (Vγ9+Vδ2+) acquired a dual phenotype characteristic for both APCs and effector memory T cells. Coincubation of activated γδ T cells pulsed with HLA-restricted epitopes of either the highly stimulatory EBV lytic cycle antigen BZLF-1 or the tumor-associated latent EBV antigen LMP2a with autologous peripheral blood lymphocytes induced selective expansion of peptide-specific, fully functional CD3+CD8+ cytolytic effector memory T cells. Furthermore, γδ T-APCs efficiently processed and presented endogenous antigen, as demonstrated by the capacity of LMP2a gene-transduced γδ T cells to induce expansion of T cells with broad specificity for various LMP2a peptides. The capacity of autologous γδ T cells to induce LMP2a-specific autologous CTLs was confirmed in two patients with Hodgkin lymphoma. In summary, bisphosphonate-activated human γδ T cells stimulate expansion of cytotoxic effector T cells specific for both subdominant and dominant viral epitopes and thus show promise as a novel source of efficient APCs for immunotherapy of viral and malignant disease.