Granzyme B Contributes to the Optimal Graft-Versus-Tumor Effect Mediated by Conventional CD4+ T Cells
Granzyme B Contributes to the Optimal Graft-Versus-Tumor Effect Mediated by Conventional CD4+ T Cells
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发表时间：
2016-04
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通讯作者：
W. Du;Nicholas D. Leigh;Guanglin Bian;E. Alqassim;R. O’Neill;Lin Mei;Jingxin Qiu;Hong Liu;P. McCarthy;Xuefang Cao
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作者：
W. Du;Nicholas D. Leigh;Guanglin Bian;E. Alqassim;R. O’Neill;Lin Mei;Jingxin Qiu;Hong Liu;P. McCarthy;Xuefang Cao
颗粒酶B （Granzyme B, GzmB）是T细胞杀灭病原体感染细胞或转化肿瘤细胞的关键细胞毒分子。先前使用同种异体造血细胞移植（alloo - hct）小鼠模型的研究表明，GzmB是CD8+ T细胞引起移植物抗宿主病（GVHD）所必需的。然而，我们最近的研究表明，gzmb介导的CD8+ T细胞损伤降低了它们的移植物抗肿瘤（GVT）活性。在这项研究中，我们检测了GzmB在常规CD4+CD25−T细胞（CD4+ Tcon）介导的GVT效应中的作用。与野生型（WT） CD4+ Tcon细胞相比，GzmB−/−CD4+ Tcon细胞的GVT活性降低，这表明GzmB是CD4+ Tcon细胞最佳GVT活性所必需的。另一方面，GzmB−/−CD4+CD25+调节性T细胞在抑制GVT活性方面与WT调节性T细胞一样具有抑制作用，这与我们之前的报道一致，即GzmB不需要调节性T细胞介导的GVHD抑制。这些结果表明，GzmB对CD4+CD25−和CD8+ T细胞介导的GVT作用产生相反的影响。有趣的是，GzmB−/−总T细胞表现出与WT总T细胞相当的GVT活性，这表明GzmB对CD4+CD25−和CD8+ T细胞的GVT效应的相反影响可能相互中和，这只能在检查单个T细胞亚群时观察到。重要的是，这些不同的作用表明，靶向选择性T细胞亚群中的GzmB可能有可能增强有益的GVT作用。
Granzyme B (GzmB) is a key cytotoxic molecule utilized by T cells to kill pathogen-infected cells or transformed tumor cells. Previous studies using allogeneic hematopoietic cell transplantation (allo-HCT) murine models showed that GzmB is required for CD8+ T cells to cause graft-versus-host disease (GVHD). However, our recent study demonstrated that GzmB-mediated damage of CD8+ T cells diminished their graft-versus-tumor (GVT) activity. In this study, we examined the role of GzmB in GVT effect mediated by conventional CD4+CD25− T cells (CD4+ Tcon). GzmB−/−CD4+ Tcon cells exhibited decreased GVT activity compared to wild-type (WT) CD4+ Tcon cells, suggesting that GzmB is required for the optimal GVT activity of CD4+ Tcon cells. On the other hand, GzmB−/− CD4+CD25+ regulatory T cells were as suppressive as WT regulatory T cells in suppressing GVT activity, which is consistent with our previous report showing that GzmB is not required for regulatory T cell-mediated suppression of GVHD. These results demonstrate that GzmB causes opposite impacts on GVT effect mediated by CD4+CD25− versus CD8+ T cells. Interestingly, GzmB−/− total T cells exhibited GVT activity equivalent to that of WT total T cells, suggesting that the opposite impacts of GzmB on the GVT effect of CD4+CD25− versus CD8+ T cells may neutralize each other, which can only be observed when an individual T cell subset is examined. Importantly, these differential roles suggest that targeting GzmB in selective T cell subsets may have the potential to enhance the beneficial GVT effect.