Phosphoantigens Overcome Human TCRVγ9+ γδ Cell Immunosuppression by TGF-β: Relevance for Cancer Immunotherapy
Phosphoantigens Overcome Human TCRVγ9+ γδ Cell Immunosuppression by TGF-β: Relevance for Cancer Immunotherapy
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DOI：
10.4049/jimmunol.1000681
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发表时间：
2010-06-15
影响因子：
4.4
通讯作者：
Fournie, Jean-Jacques
中科院分区：
文献类型：
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作者：
Capietto, Aude-Helene;Martinet, Ludovic;Fournie, Jean-Jacques
表达TCRV γ 9的人γ δ细胞是HLA非限制性CTL，与癌症免疫治疗高度相关。许多肿瘤细胞类型产生TGF-β，然而，TGF-β是一种对常规T CD 4、CD 8和NK细胞具有强烈免疫抑制作用的细胞因子。TGF-β是否也抑制TCRV γ 9（+）淋巴细胞尚不清楚。由于磷酸化抗原（PAg），如溴代醇焦磷酸，选择性激活TCRV γ 9（+）T细胞的抗肿瘤功能，在这项研究中，我们研究了TGF-β是否调节这些功能。我们报告说，TGF-β不阻断TCRV γ 9（+）T细胞的活化，但抑制其PAg/IL-2诱导的增殖和成熟为效应细胞，并最终降低这些γ δ T细胞暴露于淋巴瘤靶细胞时的细胞毒活性。TGF-β并不使它们的分化模式偏向γ δ Th 17或γ δ调节性T细胞。然而，增加剂量的PAg刺激对抗TGF-β抑制。因此，尽管TGF-β像其他溶细胞淋巴细胞一样损害TCRV γ 9（+）γ δ细胞，但单独的PAg或与治疗性mAb组合的PAg具有绕过其免疫抑制活性的能力。免疫学杂志，2010，184：6680-6687。
Human gamma delta cells expressing TCRV gamma 9 are HLA-unrestricted CTLs with high relevance for cancer immunotherapy. Many tumor cell types produce TGF-beta, however, a cytokine strongly immunosuppressive for conventional T CD4, CD8, and NK cells. Whether TGF-beta also inhibits TCRV gamma 9(+) lymphocytes was unknown. Because phosphoantigens (PAgs), such as bromohydrin pyrophosphate, selectively activate the antitumor functions of TCRV gamma 9(+) T cells, in this study, we investigated whether TGF-beta modulates these functions. We report that TGF-beta does not block activation of TCRV gamma 9(+) T cells but inhibits their PAg/IL-2-induced proliferation and maturation into effector cells and finally reduces the cytotoxic activity of these gamma delta T cells when exposed to lymphoma target cells. TGF-beta did not bias their differentiation pattern toward gamma delta Th17 or gamma delta regulatory T cells. Nevertheless, increasing doses of PAg stimulus countered TGF-beta inhibition. So, although TGF-beta impairs TCRV gamma 9(+) gamma delta cells like other cytolytic lymphocytes, PAg alone or combined to therapeutic mAb has the ability to bypass its immunosuppressive activity. The Journal of Immunology, 2010, 184: 6680-6687.