Delayed functional maturation of natural regulatory T cells in the medulla of postnatal thymus: role of TSLP.
Delayed functional maturation of natural regulatory T cells in the medulla of postnatal thymus: role of TSLP.
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DOI：
10.1186/1471-2172-7-6
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发表时间：
2006-04-03
期刊：
影响因子：
3
通讯作者：
Su, Lishan
中科院分区：
文献类型：
--
作者：
Jiang, Qi;Su, Hua;Knudsen, Geoffry;Helms, Whitney;Su, Lishan
小鼠胸腺中功能性CD 4 + CD 8-CD 25+调节性T细胞（Treg）的产生依赖于FoxP 3。从新生小鼠中去除胸腺已显示导致多器官自身免疫性疾病表型，其可通过将FoxP 3 + Treg群体引入动物来预防。因此，有人提出功能性FoxP 3 + Treg细胞不是在新生儿胸腺中产生的;然而，目前尚不清楚出生后胸腺中何时以及何处产生功能性FoxP 3 + CD 4 + CD 8-CD 25+胸腺细胞。我们报道，FoxP 3 mRNA和蛋白质在出生后3-4天在CD 4 + CD 8-CD 25+或CD 4 + CD 8-CD 25-胸腺细胞中均不表达，尽管出生后1-2天在胸腺中存在成熟的CD 4 + CD 8-CD 25 +/-胸腺细胞。来自第2天新生小鼠的FoxP 3-CD 4 + CD 8-CD 25+胸腺细胞不显示Treg活性。有趣的是，我们能够检测到低数量的FoxP 3+胸腺细胞分散在整个胸腺的髓质区域早在出生后3-4天。在体外培养4-6天后，在胚胎第17天的胎儿胸腺器官培养物（FTOC）中诱导FoxP 3的表达。用胸腺基质衍生的淋巴细胞生成素（TSLP）处理FTOC可增强FoxP 3的表达，阻断TSLP受体可降低FTOC中FoxP 3的表达。此外，TSLP刺激FoxP 3在纯化的CD 4 + CD 8-胸腺细胞中的表达，但不刺激CD 4 + CD 8+、CD 4-CD 8+和CD 4-CD 8-胸腺细胞中的表达。FoxP 3或Treg成熟的表达在个体发生学上与出生后胸腺中的CD 4 + CD 8-CD 25+或CD 4 + CD 8-CD 25-胸腺细胞的产生不同并且在动力学上延迟。胸腺髓质上皮细胞（mTEC）产生的TSLP有助于FoxP 3的表达和天然调节性T细胞的成熟。总体而言，这些结果表明，Treg细胞的发育需要在胸腺细胞成熟的晚期阶段的旁分泌信号传导，这与阳性或阴性选择期间的信号传导不同。
Generation of functional CD4+CD8-CD25+ regulatory T cells (Treg) in the murine thymus depends on FoxP3. Removal of the thymus from neonatal mice has been shown to result in a multiple organ autoimmune disease phenotype that can be prevented by introducing the FoxP3+ Treg population to the animal. It has therefore, been proposed that functional FoxP3+ Treg cells are not made in the neonatal thymus; however, it remains unclear when and where functional FoxP3+CD4+CD8-CD25+ thymocytes are generated in postnatal thymus. We report that neither FoxP3 mRNA nor protein is expressed in CD4+CD8-CD25+, or CD4+CD8-CD25- thymocytes until 3–4 days post birth, despite the presence of mature CD4+CD8-CD25+/- thymocytes in the thymus by 1–2 days after birth. FoxP3-CD4+CD8-CD25+ thymocytes from day 2 newborn mice show no Treg activity. Interestingly, we are able to detect low numbers of FoxP3+ thymocytes dispersed throughout the medullary region of the thymus as early as 3–4 days post birth. Expression of FoxP3 is induced in embryonic day 17 fetal thymus organ culture (FTOC) after 4–6 days of in vitro culture. Treatment of FTOCs with thymic stromal derived lymphopoietin (TSLP) enhanced expression of FoxP3, and blocking the TSLP receptor reduces FoxP3 expression in FTOC. Furthermore, TSLP stimulates FoxP3 expression in purified CD4+CD8- thymocytes, but not in CD4+CD8+, CD4-CD8+ and CD4-CD8- thymocytes. Expression of FoxP3 or Treg maturation is ontogenically distinct and kinetically delayed from the generation of CD4+CD8-CD25+ or CD4+CD8-CD25- thymocytes in the postnatal thymus. TSLP produced from medullary thymic epithelia cells (mTEC) contributes to the expression of FoxP3 and the maturation of natural regulatory T cells. Overall, these results suggest that the development of Treg cells requires paracrine signaling during late stages of thymocyte maturation that is distinct from signaling during positive or negative selection.