Skin Metabolites Define a New Paradigm in the Localization of Skin Tropic Memory T Cells.
Skin Metabolites Define a New Paradigm in the Localization of Skin Tropic Memory T Cells.
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DOI：
10.4049/jimmunol.1402961
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发表时间：
2015-07-01
期刊：
影响因子：
--
通讯作者：
Moser B
中科院分区：
文献类型：
--
作者：
McCully ML;Collins PJ;Hughes TR;Thomas CP;Billen J;O'Donnell VB;Moser B
记忆 T 细胞在人体皮肤上的定位对于长期免疫监视和维持屏障完整性至关重要。幼稚 T 细胞激活过程中 CCR8 的表达受表皮角质形成细胞衍生的皮肤特异性因子控制，而不是由常驻树突细胞控制。在这项研究中，我们证明 CCR8 诱导因子具有热稳定性和抗蛋白酶性，包括维生素 D3 代谢物 1α,25-二羟基维生素 D3 和 PGE2。任何一种代谢物单独对 CCR8 表达的影响都很弱，而它们的组合则导致 CCR8 表达强劲。细胞内 cAMP 的升高至关重要，因为 PGE2 可以被腺苷酸环化酶激动剂毛喉素取代，并且 CCR8 表达对蛋白激酶 A 抑制敏感。为了有效诱导，需要在 T 细胞激活之前或激活过程中将初始 T 细胞暴露于这些表皮因子，即使 CCR8 仅在 4-5 天后才在增殖 T 细胞中检测到。组织环境在维持不同健康组织内的细胞免疫监视网络方面的重要性提供了适应性免疫的范式转变。表皮衍生的维生素 D3 代谢物和 PG 为 CCR8+ 免疫监视 T 细胞在健康人体皮肤内的定位提供了重要线索。
The localization of memory T cells to human skin is essential for long-term immune surveillance and the maintenance of barrier integrity. The expression of CCR8 during naive T cell activation is controlled by skin-specific factors derived from epidermal keratinocytes and not by resident dendritic cells. In this study, we show that the CCR8-inducing factors are heat stable and protease resistant and include the vitamin D3 metabolite 1α,25-dihydroxyvitamin D3 and PGE2. The effect of either metabolite alone on CCR8 expression was weak, whereas their combination resulted in robust CCR8 expression. Elevation of intracellular cAMP was essential because PGE2 could be substituted with the adenylyl cyclase agonist forskolin, and CCR8 expression was sensitive to protein kinase A inhibition. For effective induction, exposure of naive T cells to these epidermal factors needed to occur either prior to or during T cell activation even though CCR8 was only detected 4–5 d later in proliferating T cells. The importance of tissue environments in maintaining cellular immune surveillance networks within distinct healthy tissues provides a paradigm shift in adaptive immunity. Epidermal-derived vitamin D3 metabolites and PGs provide an essential cue for the localization of CCR8+ immune surveillance T cells within healthy human skin.
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