Chongqing Key Laboratory for Diseases Proteomics, Southwest Hospital, Third Military Medical University, Chongqing, China.
J Immunol. 2010 Jul 1;185(1):126-33. doi: 10.4049/jimmunol.0903767. Epub 2010 Jun 4.
We previously demonstrated that gammadelta T cells played an important role in tumor immune surveillance by providing an early source of IFN-gamma. The precise role of different subsets of gammadelta T cells in the antitumor immune response, however, is unknown. Vgamma1 and Vgamma4 gammadelta T cells are the principal subsets of peripheral lymphoid gammadelta T cells and they might play distinct roles in tumor immunity. In support of this, we observed that reconstitution of TCRdelta(-/-) mice with Vgamma4, but not Vgamma1, gammadelta T cells restored the antitumor response. We also found that these effects were exerted by the activated (CD44(high)) portion of Vgamma4 gammadelta T cells. We further determined that IFN-gamma and perforin are critical elements in the Vgamma4-mediated antitumor immune response. Indeed, CD44(high) Vgamma4 gammadelta T cells produced significantly more IFN-gamma and perforin on activation, and showed greater cytolytic activity than did CD44(high) Vgamma1 gammadelta T cells, apparently due to the high level of eomesodermin (Eomes) in these activated Vgamma4 gammadelta T cells. Consistently, transfection of dominant-negative Eomes in Vgamma4 gammadelta T cells diminished the level of IFN-gamma secretion, indicating a critical role of Eomes in the effector function of these gammadelta T cells. Our results thus reveal distinct functions of Vgamma4 and Vgamma1 gammadelta T cells in antitumor immune response, and identify a protective role of activated Vgamma4 gammadelta T cells, with possible implications for tumor immune therapy.
我们之前的研究表明，γδ T 细胞通过提供早期 IFN-γ 来源，在肿瘤免疫监视中发挥重要作用。然而，不同γδ T 细胞亚群在抗肿瘤免疫反应中的确切作用尚不清楚。Vγ1 和 Vγ4 γδ T 细胞是外周淋巴组织中 γδ T 细胞的主要亚群，它们可能在肿瘤免疫中发挥不同的作用。我们观察到，用 Vγ4 γδ T 细胞而不是 Vγ1 γδ T 细胞重建 TCRδ(-/-) 小鼠可以恢复抗肿瘤反应，这支持了上述观点。我们还发现，这些作用是由 Vγ4 γδ T 细胞的激活（CD44(high)）部分发挥的。我们进一步确定 IFN-γ 和穿孔素是 Vγ4 介导的抗肿瘤免疫反应的关键因素。事实上，CD44(high) Vγ4 γδ T 细胞在激活时产生的 IFN-γ 和穿孔素明显更多，并且比 CD44(high) Vγ1 γδ T 细胞具有更强的细胞毒性活性，这显然是由于这些激活的 Vγ4 γδ T 细胞中高水平的 eomesodermin（Eomes）。一致地，在 Vγ4 γδ T 细胞中转染显性负性 Eomes 可降低 IFN-γ 分泌水平，表明 Eomes 在这些 γδ T 细胞的效应功能中起关键作用。我们的研究结果因此揭示了 Vγ4 和 Vγ1 γδ T 细胞在抗肿瘤免疫反应中的不同功能，并确定了激活的 Vγ4 γδ T 细胞的保护作用，这可能对肿瘤免疫治疗具有重要意义。
