Effector function of diabetogenic CD4 Th1 T cell clones:: A central role for TNF-α
Effector function of diabetogenic CD4 Th1 T cell clones:: A central role for TNF-α
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DOI：
10.4049/jimmunol.175.11.7738
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发表时间：
2005-12-01
影响因子：
4.4
通讯作者：
Haskins, K
中科院分区：
文献类型：
--
作者：
Cantor, J;Haskins, K
T细胞在自身免疫性糖尿病中的效应子功能已经用离体刺激的淋巴T细胞的混合群体进行了广泛的研究，但是这种方法不允许评估发病过程中炎症部位中单个T细胞克隆的贡献。我们已经调查了细胞因子的生产在体外和体内的一个面板的致糖尿病的CD 4 Th 1 T细胞克隆来自NOD小鼠。SuperArray分析显示了TCR刺激后体外炎性细胞因子和受体的mRNA表达的共同模式。离体细胞内细胞因子染色表明，两个重要的炎性细胞因子，IFN-γ和TNF-α，是由这些T细胞回收的胰腺过继转移后6天。由致病性T细胞克隆和募集的巨噬细胞在胰腺中产生的TNF-α不是膜结合形式。分泌的TNF-α可导致多种炎性趋化因子的产生，如通过细胞内细胞因子染色在致病性克隆中观察到的。我们的研究结果不仅定义了对糖尿病发展至关重要的炎性细胞因子反应的性质，而且还表明其在CD 4 T细胞诱导的发病过程中调节其他事件的作用。在其他模型中的类似分析表明，由CD 4 T细胞克隆诱导的疾病与需要CD 4和CD 8 T细胞的自发性自身免疫性糖尿病非常相似。因此，克隆的T细胞实际上扩增了T细胞的效应子功能，否则在没有离体刺激的情况下可能难以检测到T细胞的效应子功能。
Effector function of T cells in autoimmune diabetes has been widely studied with mixed populations of lymphoid T cells stimulated ex vivo, but this approach does not permit evaluation of the contribution by a single T cell clone in the inflammatory site during pathogenesis. We have investigated cytokine production both in vitro and in vivo in a panel of diabetogenic CD4 Th1 T cell clones derived from the NOD mouse. SuperArray analysis showed a common pattern of mRNA expression for inflammatory cytokines and receptors in vitro after TCR stimulation. Ex vivo intracellular cytokine staining demonstrated that two important inflammatory cytokines, IFN-gamma and TNF-alpha, were being made by these T cells recovered from the pancreas 6 days following adoptive transfer. TNF-a produced in the pancreas by pathogenic T cell clones and recruited macrophages was not the membrane-bound form. Secreted TNF-a can lead to production of multiple inflammatory chemokines, as were observed in the pathogenic clones by intracellular cytokine staining. Our results not only define the nature of an inflammatory cytokine response critical to development of diabetes, but also suggest its role in the regulation of other events during pathogenesis induced by CD4 T cells. Similar analyses in other models demonstrated that disease induced by CD4 T cell clones closely resembles spontaneous autoimmune diabetes in which both CD4 and CD8 T cells are required. Thus, cloned T cells in effect amplify effector function of T cells which otherwise may be difficult to detect without ex vivo stimulation.