Schilbach Karin, Frommer Klaus, Meier Sybille, Handgretinger Rupert, Eyrich Matthias
Department of Pediatric Stem Cell Transplantation, University Children's Hospital, University of Tübingen, Tübingen, Germany.
J Immunother. 2008 Nov-Dec;31(9):896-905. doi: 10.1097/CJI.0b013e31818955ad.
Human peripheral gammadelta-T-cells are able to induce cytolysis of neuroblastoma (Nb) tumor cells. Besides innate effector functions against infected cells and tumors, gammadelta-T-cells are involved in T-helper 1/T-helper 2 (TH1/TH2) differentiation of alphabeta-T-cells. However, as different gammadelta-T-cell subsets vary considerably in their functional properties, the aim of the present study was to define repertoires of cytokines, chemokines, and angiogenic factors of in vitro expanded Vdelta1+ and Vdelta2+ T cells in response to Nb. After short-term culture, both subsets released TH1 [interleukin (IL)-2, interferon (IFN)-gamma, IL-12, tumor necrosis factor (TNF)-alpha, TNF-beta)] and TH2 cytokines (IL-4, -5, -6, -10, -13, Vdelta1 also transforming growth factor (TGF)-beta, chemokines (I-309, monocyte chemotactic protein (MCP)-1-3, regulated upon activation, normal T-cell expressed and secreted), ILs (IL-1, -8, -15), cytokines (leptin) as well as angiogenic growth factors [angiogenin (ANG), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), Insulin-like growth factor (IGF)-I]. These molecules were expressed at higher levels in Vdelta2+ than Vdelta1+ T cells. Nb challenge changed protein expression. TH2 cytokine and IFN-gamma release was blocked in both gammadelta-T-cell subsets. In Vdelta2 gammadelta-T-cells, TH1 cytokines were down-regulated and tumor growth-promoting factors (ANG, VEGF, EGF, and IGF-I) were strongly up-regulated. In contrast, Vdelta1+ gammadelta-T-cells stopped the release of tumor-supportive factors and tolerogenic TGF-beta, and strongly up-regulated TNF-alpha, TNF-beta, MCP-1 and -2 and maintained their IL-2 production. In summary, our data show that after being challenged with Nb cells, propagated Vdelta1+ rather than Vdelta2+ T cells support antitumor responses by secretion of proinflammatory cytokines. Furthermore, in contrast to other cell types, Vdelta1+ T cells do not sustain a growth-promoting or tolerogenic microenvironment. These data make Vdelta1+ T cells an ideal candidate for upcoming immunotherapy trials in Nb.
人类外周γδ-T细胞能够诱导神经母细胞瘤（Nb）肿瘤细胞的细胞溶解。除了对受感染细胞和肿瘤具有先天性效应功能外，γδ-T细胞还参与αβ-T细胞的辅助性T细胞1/辅助性T细胞2（TH1/TH2）分化。然而，由于不同的γδ-T细胞亚群在功能特性上有很大差异，本研究的目的是确定体外扩增的Vδ1+和Vδ2+ T细胞对Nb反应时细胞因子、趋化因子和血管生成因子的谱。短期培养后，两个亚群都释放了TH1[白细胞介素（IL）-2、干扰素（IFN）-γ、IL-12、肿瘤坏死因子（TNF）-α、TNF-β]和TH2细胞因子（IL-4、-5、-6、-10、-13，Vδ1还分泌转化生长因子（TGF）-β）、趋化因子（I-309、单核细胞趋化蛋白（MCP）-1-3、活化后调节、正常T细胞表达和分泌）、白细胞介素（IL-1、-8、-15）、细胞因子（瘦素）以及血管生成生长因子[血管生成素（ANG）、血管内皮生长因子（VEGF）、表皮生长因子（EGF）、胰岛素样生长因子（IGF）-I]。这些分子在Vδ2+ T细胞中的表达水平高于Vδ1+ T细胞。Nb刺激改变了蛋白质表达。两个γδ-T细胞亚群中TH2细胞因子和IFN-γ的释放均被阻断。在Vδ2 γδ-T细胞中，TH1细胞因子下调，肿瘤生长促进因子（ANG、VEGF、EGF和IGF-I）强烈上调。相反，Vδ1+ γδ-T细胞停止释放肿瘤支持因子和耐受性TGF-β，并强烈上调TNF-α、TNF-β、MCP-1和-2，并维持其IL-2的产生。总之，我们的数据表明，在用Nb细胞刺激后，扩增的Vδ1+而非Vδ2+ T细胞通过分泌促炎细胞因子来支持抗肿瘤反应。此外，与其他细胞类型不同，Vδ1+ T细胞不会维持促进生长或耐受性的微环境。这些数据使Vδ1+ T细胞成为即将开展的Nb免疫治疗试验的理想候选者。
