Granzyme B-Mediated Activation-Induced Death of CD4+ T Cells Inhibits Murine Acute Graft-versus-Host Disease.
Granzyme B-Mediated Activation-Induced Death of CD4+ T Cells Inhibits Murine Acute Graft-versus-Host Disease.
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DOI：
10.4049/jimmunol.1500668
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发表时间：
2015-11-01
期刊：
影响因子：
--
通讯作者：
Cao X
中科院分区：
文献类型：
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作者：
Du W;Leigh ND;Bian G;O'Neill RE;Mei L;Qiu J;Chen GL;Hahn T;Liu H;McCarthy PL;Cao X
颗粒酶B （GzmB）先前已被证明对CD8+ T细胞介导的移植物抗宿主病（GVHD）至关重要，但对CD4+ T细胞介导的GVHD却没有作用。然而，先前的研究在mhc错配模型中使用高剂量的CD4+ T细胞，导致快速和致命的GVHD。由于超急性致死性，GzmB的作用可能被系统所掩盖。因此，在本研究中，我们降低了T细胞剂量，以精确确定GzmB在CD4+CD25−T细胞介导的GVHD中的作用。令人惊讶的是，我们发现在mhc匹配和错配模型中，GzmB - / - CD4+CD25 - T细胞比野生型（WT） CD4+CD25 - T细胞引起更严重的GVHD。机制分析显示，虽然GzmB不影响供体T细胞的植入、增殖或组织特异性迁移，但GzmB介导的激活诱导的WT CD4+CD25−T细胞死亡导致GzmB−/−CD4+CD25−T细胞表现出显著增强的扩增。由于扩增增强，GzmB - / - T细胞产生更多的促炎细胞因子（如TNF-α和IFN-γ），这可能导致GVHD加剧。这些结果表明，GzmB降低了CD4+ T细胞引起急性GVHD的能力，这与其在CD8+ T细胞中的既定作用相矛盾。这些不同的作用表明，靶向选定T细胞亚群中的GzmB可能提供一种控制GVHD的策略。
Granzyme B (GzmB) has previously been shown to be critical for CD8+ T cell-mediated graft-versus-host disease (GVHD) but dispensable for GVHD mediated by CD4+ T cells. However, previous studies used high doses of CD4+ T cells in MHC-mismatched models that caused rapid and lethal GVHD. Due to the hyperacute lethality, it is possible that the role of GzmB was concealed by the system. Therefore, in this study we have titrated down the T cell dose to precisely determine the contribution of GzmB in GVHD mediated by CD4+CD25− T cells. Surprisingly, we have found that GzmB−/− CD4+CD25− T cells cause more severe GVHD compared to wild-type (WT) CD4+CD25− T cells in both MHC-matched and mismatched models. Mechanistic analyses reveal that while GzmB does not affect donor T cell engraftment, proliferation or tissue-specific migration, GzmB−/− CD4+CD25− T cells exhibit significantly enhanced expansion due to GzmB-mediated activation-induced cell death of WT CD4+CD25− T cells. As a result of enhanced expansion, GzmB−/− T cells produced higher amounts of proinflammatory cytokines (e.g., TNF-α and IFN-γ) that may contribute to the exacerbated GVHD. These results reveal that GzmB diminishes the ability of CD4+ T cells to cause acute GVHD, which contradicts its established role in CD8+ T cells. The differential roles suggest that targeting GzmB in selected T cell subsets may provide a strategy to control GVHD.