Function of Dendritic cells as Sentinel and Regulator

树突状细胞(DC)根据其表型和发育谱系分为几个亚群，其功能受生理环境的调控。在本研究中，我们通过实验阐明了DC在体内控制免疫应答中的作用，并获得了以下结果：1)在Id2^&lt；-/-&gt；中观察到明显偏离Th2。我们发现CD8α^+DC亚群的选择性和显著减少，它比CD8α^-DC亚群具有更高的产生IL-12的潜力。这些结果表明，Id2对于CD8IRF~+DC的正常发育是不可或缺的，而CD8IRF~+DC在α/Th2平衡的调节中起着关键作用。此外，IRF-2^&lt；-/-&gt；小鼠的表皮朗格汉斯细胞数量减少。体外逆转录病毒介导的基因转导研究表明，…需要irf-2作为细胞自主调节因子。更多的是CD4^+CD11b^+DC的发育。值得注意的是，在缺乏Irf-2和干扰素-α/β受体的小鼠中，DC亚群中的这些异常减少，表明Irf-2通过负的干扰素-α/β信号发挥作用。3)体内DCs主动内吞CFSE标记的凋亡细胞，但只有CD8CD8α^+亚群。在摄取后，CD8CD8α^+树突状细胞还选择性地向CD4^+和CD8^+T细胞递送细胞相关抗原。类似的事件也发生在有教养的人身上。CD8CD8+α+DC再次选择性地占据和呈现死亡细胞。而CD8α^+和CD8α^-DC均能吞噬培养中的乳胶颗粒，且DC亚群均存在活体捕获的可溶性卵白蛋白。4)DC原位吞噬死亡细胞后，大量抗原反应性T淋巴细胞进入细胞周期，但T细胞被删除，动物开始耐受。当死亡细胞随后在感染过程中被处理时，这种无应答的途径应该防止或减少自身免疫的发展。5)我们研究了刺激培养后P-preDC的Th极化能力。IL-3处理的DC表达OX40L，但几乎不产生干扰素-α，导致产生IL-4的Th2细胞通过OX40L依赖机制优先启动。相反，病毒感染的DC促进产生干扰素-γ的Th1细胞，这取决于它们产生干扰素-α的能力，尽管它们同时表达OX40L。然而，在激活过程中，OX40L的表达水平上调，而剩余的干扰素-α产生能力下调，因此，长时间SV刺激的DC在一定程度上诱导了Th2型反应。较少

Dendritic cells (DC) are divided into several subsets by their phenotype and developmental lineage and their functions are controlled under physiological milieu. In this study, we conducted experiments to elucidate role of DC in the control of immune responses in vivo and obtained the following results.1) Significant deviation toward Th2 was observed in Id2^<-/->. We found that a selective and remarkable reduction of the CD8α^+ DC subset, which has higher potential to produce IL-12 than the CD8α^-DC subset. These results demonstrate that Id2 is indispensable for the proper development of CD8α^+ DCs, which play a critical role in the regulation of the Th1/Th2 balance.2) Mice lacking IRF-2 (IRF-2-/-mice) exhibited a marked and selective defect in the development of splenic CD4^+ CD11b^+ DC. Furthermore, the numbers of epidermal Langerhans cells in IRF-2^<-/-> mice were reduced. Studies with in vitro retrovirus-mediated gene transduction showed that IRF-2 was required cell-autonomously fo … More r the development of CD4^+ CD11b^+ DC. Notably, these abnormalities in DC subpopulations diminished in mice lacking both IRF-2 and the IFN-α/β receptor, indicating that IRF-2 acted through negatively IFN-α/β signals.3) The CFSE-labeled apoptotic cells were actively endocytosed by DCs in vivo, but only the CD8α^+ subset. Following uptake, CD8α^+ DCs also selectively present cell-associated antigens to both CD4^+ and CD8^+ T cells. Similar events take place with cultured. DCs ; CD8α+ DCs again selectively take up and present dying cells. In contrast, both CD8α^+ and CD8α^-DCs phagocytose latex particles in culture, and both DC subsets present soluble ovalbumin captured in vivo.4) Following ingestion of the dead cells by DC in situ, large numbers of antigen-reactive T lymphocytes were driven into cell cycle, but then the T cells were deleted and the animals become tolerant. This, pathway to unresponsiveness should prevent or reduce the development of autoimmunity when dying cells are subsequently processed during infection.5) We investigated the Th-polarizing capacity of P-preDC after culture with stimuli. IL-3-treated DC expressed OX40L but produced almost no IFN-α, resulting in the preferential priming of IL-4-producing Th2 cells through OX40L-dependent mechanisms. In contrast, DC by viral infection promoted IFN-γ-producing Th1 cells, depending on their capacity to produce IFN-α, although they simultaneously expressed OX40L. However, the expression level of OX40L was upregulated whereas the, residual IFN-α producing ability was downregulated during activation and, consequently, the DC with prolonged SV stimulation induced Th2 responses to some extent. Less