Immunotherapy Unit, Department of Urology, Medical University of Innsbruck and K1 Center Oncotyrol-Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria.
Department of Pulmonary Medicine, University Medical Center Freiburg, 79106 Freiburg, Germany.
Cell Rep. 2016 Jul 12;16(2):444-456. doi: 10.1016/j.celrep.2016.06.009. Epub 2016 Jun 23.
In humans, Vγ9Vδ2 T cells respond to self and pathogen-associated, diphosphate-containing isoprenoids, also known as phosphoantigens (pAgs). However, activation and homeostasis of Vγ9Vδ2 T cells remain incompletely understood. Here, we show that pAgs induced expression of the ecto-ATPase CD39, which, however, not only hydrolyzed ATP but also abrogated the γδ T cell receptor (TCR) agonistic activity of self and microbial pAgs (C5 to C15). Only mevalonate-derived geranylgeranyl diphosphate (GGPP, C20) resisted CD39-mediated hydrolysis and acted as a regulator of CD39 expression and activity. GGPP enhanced macrophage differentiation in response to the tissue stress cytokine interleukin-15. In addition, GGPP-imprinted macrophage-like cells displayed increased capacity to produce IL-1β as well as the chemokine CCL2 and preferentially activated CD161-expressing CD4(+) T cells in an innate-like manner. Our studies reveal a previously unrecognized immunoregulatory function of CD39 and highlight a particular role of GGPP among pAgs.
在人类中，Vγ9Vδ2 T 细胞对自身和病原体相关的、含有二磷酸的异戊烯基化合物（也称为磷酸抗原，pAg）产生反应。然而，Vγ9Vδ2 T 细胞的激活和稳态仍不完全清楚。在这里，我们表明 pAg 诱导了外核苷酸酶 CD39 的表达，然而，CD39 不仅水解了 ATP，还削弱了自身和微生物 pAg（C5 到 C15）的 γδ T 细胞受体（TCR）激动活性。只有甲羟戊酸衍生的香叶基香叶基二磷酸（GGPP，C20）能够抵抗 CD39 介导的水解，并作为 CD39 表达和活性的调节剂。GGPP 增强了巨噬细胞对组织应激细胞因子白细胞介素-15 的分化。此外，GGPP 印迹的巨噬样细胞显示出增加的产生 IL-1β 以及趋化因子 CCL2 的能力，并以固有样方式优先激活表达 CD161 的 CD4(+) T 细胞。我们的研究揭示了 CD39 的一个以前未被认识的免疫调节功能，并强调了 GGPP 在 pAg 中的一个特殊作用。
