Ability of mature dendritic cells to interact with regulatory T cells is imprinted during maturation.
Ability of mature dendritic cells to interact with regulatory T cells is imprinted during maturation.
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DOI：
10.1158/0008-5472.can-07-6818
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发表时间：
2008-07-15
期刊：
影响因子：
11.2
通讯作者：
Kalinski P
中科院分区：
文献类型：
--
作者：
Muthuswamy R;Urban J;Lee JJ;Reinhart TA;Bartlett D;Kalinski P
在慢性免疫反应中，调节性T （Treg）细胞的优先激活限制了自身免疫组织的损伤，但也可以促进肿瘤的生长。在这里，我们发现组织产生的炎症介质促进成熟树突状细胞（DC）吸引抗炎Treg细胞的不同能力。我们的数据显示，前列腺素E2 （PGE2）是一种在慢性炎症和癌症中过量产生的因子，在CCL22介导的成熟DC中诱导稳定的treg吸引特性。PGE2成熟的DC在去除PGE2后仍能提高CCL22的产量，并在中性环境中对DC进行二次刺激后进一步提高。这种pge2诱导的CCL22的过量产生和FOXP3+ treg的吸引被IFNα抵消，IFNα是急性炎症的介质，它也恢复了pge2暴露的DC分泌th1吸引趋化因子的能力：CXCL9、CXCL10、CXCL11和CCL5。根据这些观察，临床使用的不同DC作为癌症疫苗表现出不同的treg招募能力，在I型和II型ifn存在下产生的pge2成熟DC，而不是1型极化DC，表现出高的treg吸引活性。目前的数据显示，成熟DC与Treg细胞相互作用的能力在DC成熟阶段是预先确定的，这为在自身免疫和移植中优先靶向调节性T细胞和促炎T细胞铺平了道路，而不是细胞内感染和癌症。
Preferential activation of regulatory T (Treg) cells limits autoimmune tissue damage during chronic immune responses but can also facilitate tumor growth. Here, we show that tissue-produced inflammatory mediators prime maturing dendritic cells (DC) for the differential ability of attracting anti-inflammatory Treg cells. Our data show that prostaglandin E2 (PGE2), a factor overproduced in chronic inflammation and cancer, induces stable Treg-attracting properties in maturing DC, mediated by CCL22. The elevated production of CCL22 by PGE2-matured DC persists after the removal of PGE2 and is further elevated after secondary stimulation of DC in a neutral environment. This PGE2-induced overproduction of CCL22 and the resulting attraction of FOXP3+ Tregs are counteracted by IFNα, a mediator of acute inflammation, which also restores the ability of the PGE2-exposed DC to secrete the Th1-attracting chemokines: CXCL9, CXCL10, CXCL11, and CCL5. In accordance with these observations, different DCs clinically used as cancer vaccines show different Treg-recruiting abilities, with PGE2-matured DC, but not type 1–polarized DC, generated in the presence of type I and type II IFNs, showing high Treg-attracting activity. The current data, showing that the ability of mature DC to interact with Treg cells is predetermined at the stage of DC maturation, pave the way to preferentially target the regulatory versus proinflammatory T cells in autoimmunity and transplantation, as opposed to intracellular infections and cancer.