Cytokine-induced human IFN-γ-secreting effector-memory Th cells in chronic autoimmune inflammation
Cytokine-induced human IFN-γ-secreting effector-memory Th cells in chronic autoimmune inflammation
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DOI：
10.1182/blood-2008-02-139147
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发表时间：
2009-02-26
期刊：
影响因子：
20.3
通讯作者：
Thiel, Andreas
中科院分区：
文献类型：
--
作者：
Sattler, Arne;Wagner, Ulf;Thiel, Andreas
在没有T细胞受体连接的情况下，由细胞因子激活的辅助性T细胞(Th)可能通过产生干扰素-γ(IFN-Gamma)参与炎症过程。尽管如此，这种机制的相关性还没有在人类身上得到解决。在这里，我们证明了体外表达功能性白介素12R(IL-12R)、IL-18Rα和CCR5的人效应记忆Th细胞亚群可以通过IL-2R共同的伽马链与IL-12和IL-18结合的细胞因子信号诱导分泌干扰素-γ。细胞因子驱动的干扰素-γ的产生依赖于JAK3和p38丝裂原激活的激酶信号，并且对CD25(++)调节性T细胞的抑制很敏感。与抗原特异性刺激诱导的干扰素-γ(+)Th细胞相反，它们的细胞因子激活的Th细胞缺乏共刺激分子4-1BB(CD137)的表达。值得注意的是，大多数类风湿性关节炎患者炎症关节中的Th细胞都配备了细胞因子诱导的干扰素-γ分泌所必需的受体。在这些细胞中，我们检测到相当一部分细胞在体外直接分泌干扰素-γ，但缺乏4-1BB的表达，表明细胞因子诱导的干扰素-γ(+)Th细胞在自身免疫性炎症中发挥作用。我们的数据为人类效应记忆T细胞如何参与自身免疫中持久的炎症过程提供了理论基础，即使在没有T细胞受体连接的情况下也是如此。(血。2009年；113：1948-1956)
T-helper (Th) cells activated by cytokines in the absence of T-cell receptor ligation are suspected to participate in inflammatory processes by production of interferon-gamma (IFN-gamma). Still, the relevance of such a mechanism has not been addressed in humans. Here we demonstrate that a subset of human effector-memory Th cells expressing functional interleukin-12R (IL-12R), IL-18R alpha, and CCR5 ex vivo can be induced to secrete IFN-gamma by cytokines signaling via the IL-2R common gamma-chain in combination with IL-12 and IL-18. Cytokine-driven IFN-gamma production depends on JAK3- and p38 mitogen-activated kinase signals and is sensitive to suppression by CD25(++) regulatory T cells. Contrary to IFN-gamma(+) Th cells induced upon antigen-specific stimulation, their cytokine-activated counterparts characteristically lack expression of costimulator 4-1BB (CD137). Strikingly, the majority of Th cells infiltrating inflamed joints of rheumatoid arthritis patients is equipped with receptors prerequisite for cytokine-induced IFN-gamma secretion. Among these cells, we detected a substantial fraction that secretes IFN-gamma directly ex vivo but lacks 4-1BB expression, indicating that cytokine-induced IFN-gamma(+) Th cells operate in autoimmune inflammation. Our data provide a rationale for how human effector-memory Thcells can participate in perpetuating inflammatory processes in autoimmunity even in the absence of T-cell receptor ligation. (Blood. 2009; 113: 1948-1956)