Autoimmune regulator deficiency results in decreased expression of CCR4 and CCR7 ligands and in delayed migration of CD4+ thymocytes.
Autoimmune regulator deficiency results in decreased expression of CCR4 and CCR7 ligands and in delayed migration of CD4+ thymocytes.
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DOI：
10.4049/jimmunol.0804133
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发表时间：
2009-12-15
期刊：
影响因子：
--
通讯作者：
Peterson P
中科院分区：
文献类型：
--
作者：
Laan M;Kisand K;Kont V;Möll K;Tserel L;Scott HS;Peterson P
自身免疫调节因子（Aire）被认为是诱导耐受的核心参与者。本研究探讨，Aire是否可以调节参与皮质-髓质迁移的胸腺趋化因子的产生，从而在胸腺内胸腺细胞迁移和成熟中发挥作用。通过定量PCR分析和ELISA测定，Aire缺乏导致小鼠整个胸腺中CCR 4和CCR 7配体的基因表达和蛋白水平降低。CCR 4配体的表达与Aire在CD 80高髓质上皮细胞（mTECs）中的表达一致，而CCR 7配体的表达在其他细胞群体中检测到。此外，CCR 4和CCR 7配体的表达模式遵循出生后的Aire，但不是在胚胎发育过程中。在体外，Aire的过表达导致选定的CCR 4和CCR 7配体的上调，这诱导了双阳性（DP）和单阳性（SP）CD 4+细胞的选择性迁移。在体内，Aire缺乏导致5日龄小鼠胸腺中成熟CD 4 + T细胞的迁出减少。总之，Aire调节mTEC中CCR 4和CCR 7配体的产生，并改变胸腺细胞的协调成熟和迁移。这些结果表明，一种新的机制背后的Aire依赖性诱导中枢耐受。
Autoimmune regulator (Aire) has been viewed as a central player in the induction of tolerance. This study examines, whether Aire can modulate the production of the thymic chemokines involved in cortico-medullary migration and thus play a role in intrathymic thymocyte migration and maturation. Aire deficiency resulted in reduced gene expression and protein levels of the CCR4 and CCR7 ligands in whole thymi of mice, as determined by quantitative PCR analysis and ELISA. The expression of the CCR4 ligands coincided with Aire expression in the CD80high medullary epithelial cells (mTECs), whereas the expression of the CCR7 ligands was detected in other cell populations. Also, the expression pattern of the CCR4 and CCR7 ligands follows that of Aire during postnatal but not during embryonic development. In vitro, overexpression of Aire resulted in an upregulation of selected CCR4 and CCR7 ligands, which induced selective migration of double-positive (DP) and single positive (SP) CD4+ cells. In vivo, Aire deficiency resulted in a diminished emigration of mature CD4+ T-cells from the thymi of 5-day-old mice In conclusion, Aire regulates the production of CCR4 and CCR7 ligands in mTECs and alters the coordinated maturation and migration of thymocytes. These results suggest a novel mechanism behind the Aire-dependent induction of central tolerance.
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DOI：
10.1126/science.1159407
发表时间：
2008-08-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gardner JM;Devoss JJ;Friedman RS;Wong DJ;Tan YX;Zhou X;Johannes KP;Su MA;Chang HY;Krummel MF;Anderson MS
通讯作者：
Anderson MS
DOI：
10.4049/jimmunol.181.8.5225
发表时间：
2008-10-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Dooley J;Erickson M;Farr AG
通讯作者：
Farr AG
影响因子：
56.9
作者：
Anderson, MS;Venanzi, ES;Mathis, D
通讯作者：
Mathis, D
影响因子：
30.5
作者：
Derbinski, J;Schulte, A;Klein, L
通讯作者：
Klein, L
影响因子：
15.3
作者：
MIZUOCHI, T;KASAI, M;HIROKAWA, K
通讯作者：
HIROKAWA, K