Function of the IL-2R for thymic and peripheral CD4+CD25+ Foxp3+ T regulatory cells
Function of the IL-2R for thymic and peripheral CD4+CD25+ Foxp3+ T regulatory cells
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DOI：
10.4049/jimmunol.178.7.4062
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发表时间：
2007-04-01
影响因子：
4.4
通讯作者：
Malek, Thomas R.
中科院分区：
文献类型：
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作者：
Bayer, Allison L.;Yu, Aixin;Malek, Thomas R.
IL-2有助于CD 4（+）CD 25（+）T-reg细胞的产生、功能和稳态。然而，它仍然不确定是否IL-2是必不可少的胸腺中的T-reg细胞的发展，他们在周边的稳态，或两者兼而有之。本研究旨在探讨IL-2在胸腺T-reg细胞发育过程中的作用及其在外周免疫组织中的维持。依赖于遗传小鼠模型，其中IL-2 R信号传导在外周CD 4（+）CD 25（+）T-reg细胞中被完全阻断或选择性抑制，我们表明，在T-reg细胞发育的最早阶段，IL-2/IL-2 R相互作用在胸腺中是活跃的，以促进其扩增并将Foxp 3和CD 25上调至正常水平。此外，具有受损的IL-2诱导的信号传导的CD 4（+）CD 25（+）Foxp 3（+）T-reg细胞在外周中持续存在，并且控制自身免疫而没有恒定的胸腺输出。这些对IL-2反应性差的外周T-reg细胞在体内表现出较慢的生长和延长的存活，在体外表现出较低的抑制活性和较差的IL-2依赖性存活。混合的胸腺和骨髓嵌合小鼠表明，野生型衍生的T-reg细胞在外周免疫组织中比IL-2信号传导受损的T-reg细胞更有效。总的来说，这些数据支持这样的观点，即通常IL-2是控制胸腺和外周T-reg细胞数量的主导机制。
IL-2 contributes to the production, function, and homeostasis of CD4(+)CD25(+) T-reg cells. However, it remains uncertain whether IL-2 is essential for the development of T-reg cells in the thymus, their homeostasis in the periphery, or both. The present study was undertaken to investigate the contribution of IL-2 during thymic T-reg cell development and its maintenance in peripheral immune tissue. Relying on genetic mouse models where IL-2R signaling was either completely blocked or selectively inhibited in peripheral CD4(+)CD25(+) T-reg cells, we show that the IL-2/IL-2R interaction is active in the thymus at the earliest stage of the development of T-reg cells to promote their expansion and to up-regulate Foxp3 and CD25 to normal levels. Furthermore, CD4(+)CD25(+)Foxp3(+) T-reg cells with impaired IL-2-induced signaling persist in the periphery and control autoimmunity without constant thymic output. These peripheral T-reg cells with poor responsiveness to IL-2 exhibited slower growth and extended survival in vivo, somewhat lower suppressive activity, and poor IL-2-dependent survival in vitro. Mixed thymic and bone marrow chimeric mice showed that wild-type-derived T-reg cells were substantially more effective in populating peripheral immune tissue than T-reg cells with impaired IL-2 signaling. Collectively, these data support the notion that normally IL-2 is a dominant mechanism controlling the number of thymic and peripheral T-reg cells.