Inhibition of phosphoantigen-mediated γδ T-cell proliferation by CD4+ CD25+ FoxP3+ regulatory T cells
Inhibition of phosphoantigen-mediated γδ T-cell proliferation by CD4+ CD25+ FoxP3+ regulatory T cells
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DOI：
10.1111/j.1365-2567.2008.02894.x
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发表时间：
2009-02-01
期刊：
影响因子：
6.4
通讯作者：
Wilhelm, Martin
中科院分区：
文献类型：
--
作者：
Kunzmann, Volker;Kimmel, Brigitte;Wilhelm, Martin
肿瘤生长促进 CD4(+) CD25(+) FoxP3(+) 调节性 T 细胞 (Treg) 的扩增，Treg 抑制多种免疫反应，因此可能有助于肿瘤免疫监视。在这项研究中，我们发现癌症患者中循环 Treg 频率与磷酸抗原诱导的 γ δ T 细胞增殖之间存在负相关，这促使我们研究 Tregs 在控制先天免疫反应的 γ δ T 细胞臂中的作用。在体外，人 Treg 与外周血单核细胞 (PBMC) 共培养物强烈抑制磷酸抗原诱导的 γ δ T 细胞增殖，并且 Tregs 的消耗恢复了癌症患者受损的磷酸抗原诱导的 γ δ T 细胞增殖。 Tregs 不会抑制 γδT 细胞的其他效应功能，例如细胞因子的产生或细胞毒性。我们的实验表明，Tregs 并不通过细胞-细胞接触依赖性机制介导其抑制活性，而是分泌可溶性非蛋白质因子，该因子独立于与氨基酸消耗（例如精氨酸酶减少的精氨酸和吲哚胺 2,3-双加氧酶减少的色氨酸）或一氧化氮（NO）产生相互作用的已知可溶性因子。然而，αβT 细胞的增殖活性不受 Tregs 诱导的这种细胞间接触独立的抑制活性的影响。总之，这些发现表明了一种潜在的新机制，Treg可以特异性抑制γδT细胞，并强调了将Treg抑制与随后的γδT细胞激活相结合以增强γδT细胞介导的免疫治疗的策略。
Tumour growth promotes the expansion of CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) which suppress various arms of immune responses and might therefore contribute to tumour immunosurveillance. In this study, we found an inverse correlation between circulating Treg frequencies and phosphoantigen-induced gamma delta T-cell proliferation in cancer patients, which prompted us to address the role of Tregs in controlling the gamma delta T-cell arm of innate immune responses. In vitro, human Treg-peripheral blood mononuclear cell (PBMC) co-cultures strongly inhibited phosphoantigen-induced proliferation of gamma delta T cells and depletion of Tregs restored the impaired phosphoantigen-induced gamma delta T-cell proliferation of cancer patients. Tregs did not suppress other effector functions of gamma delta T cells such as cytokine production or cytotoxicity. Our experiments indicate that Tregs do not mediate their suppressive activity via a cell-cell contact-dependent mechanism, but rather secrete a soluble non-proteinaceous factor, which is independent of known soluble factors interacting with amino acid depletion (e.g. arginase-diminished arginine and indolamine 2,3-dioxygenase-diminished tryptophan) or nitric oxide (NO) production. However, the proliferative activity of alpha beta T cells was not affected by this cell-cell contact-independent suppressive activity induced by Tregs. In conclusion, these findings indicate a potential new mechanism by which Tregs can specifically suppress gamma delta T cells and highlight the strategy of combining Treg inhibition with subsequent gamma delta T-cell activation to enhance gamma delta T cell-mediated immunotherapy.