Mesenchymal stem cell inhibition of T-helper 17 cell-differentiation is triggered by cell-cell contact and mediated by prostaglandin E2 via the EP4 receptor
Mesenchymal stem cell inhibition of T-helper 17 cell-differentiation is triggered by cell-cell contact and mediated by prostaglandin E2 via the EP4 receptor
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DOI：
10.1002/eji.201141499
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发表时间：
2011-10-01
影响因子：
5.4
通讯作者：
Griffin, Matthew D.
中科院分区：
文献类型：
--
作者：
Duffy, Michelle M.;Pindjakova, Jana;Griffin, Matthew D.
间充质干细胞(MSCs)抑制T细胞的激活和增殖，但它们对单个T细胞效应器通路以及对记忆和初始T细胞的影响尚不清楚。检测MSC对初始和记忆性CD4(+)T细胞向Th17表型分化的影响。暴露在Th17偏斜条件下的CD4(+)T细胞在MSC共培养后CD25和IL-17A的表达减少。在没有MSCs的情况下，再次刺激对IL-17A产生的抑制作用持续存在。当细胞与细胞之间的接触被阻止时，这些影响被减弱。来自高度纯化的幼稚和记忆表型反应者的Th17培养也受到类似的抑制。MSCs对Th17的抑制可被吲哚美辛和选择性COX-2抑制剂逆转。MSC/Th17共培养上清液中前列腺素E2(PGE2)水平升高，并有效抑制新鲜培养中Th17的分化。MSC介导的Th17抑制可被选择性EP4拮抗剂逆转，并可被合成的PGE2和选择性EP4激动剂模拟。来自尿路梗阻模型的自然产生的效应记忆Th17细胞的激活诱导的IL-17A的分泌也被MSC以COX依赖的方式共培养抑制。总体而言，MSCs有效地抑制了来自幼稚和记忆性T细胞前体的Th17分化，并抑制了来自炎症部位的自然产生的Th17细胞。抑制需要依赖细胞接触的COX-2诱导，导致PGE2通过EP4直接抑制Th17。
Mesenchymal stem cells (MSCs) inhibit T-cell activation and proliferation but their effects on individual T-cell-effector pathways and on memory versus naive T cells remain unclear. MSC influence on the differentiation of naive and memory CD4(+) T cells toward the Th17 phenotype was examined. CD4(+) T cells exposed to Th17-skewing conditions exhibited reduced CD25 and IL-17A expression following MSC co-culture. Inhibition of IL-17A production persisted upon re-stimulation in the absence of MSCs. These effects were attenuated when cell-cell contact was prevented. Th17 cultures from highly purified naive- and memory-phenotype responders were similarly inhibited. Th17 inhibition by MSCs was reversed by indomethacin and a selective COX-2 inhibitor. Media from MSC/Th17 co-cultures contained increased prostaglandin E2 (PGE2) levels and potently suppressed Th17 differentiation in fresh cultures. MSC-mediated Th17 inhibition was reversed by a selective EP4 antagonist and was mimicked by synthetic PGE2 and a selective EP4 agonist. Activation-induced IL-17A secretion by naturally occurring, effector-memory Th17 cells from a urinary obstruction model was also inhibited by MSC co-culture in a COX-dependent manner. Overall, MSCs potently inhibit Th17 differentiation from naive and memory T-cell precursors and inhibit naturally-occurring Th17 cells derived from a site of inflammation. Suppression entails cell-contact-dependent COX-2 induction resulting in direct Th17 inhibition by PGE2 via EP4.