Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, England, UK.
J Exp Med. 2013 Apr 8;210(4):675-81. doi: 10.1084/jem.20122070. Epub 2013 Mar 25.
A key role of the thymic medulla is to negatively select autoreactive CD4(+) and CD8(+) thymocytes, a process important for T cell tolerance induction. However, the involvement of the thymic medulla in other aspects of αβ T cell development, including the generation of Foxp3(+) natural regulatory T cells (nTreg cells) and the continued maturation of positively selected conventional αβ T cells, is unclear. We show that newly generated conventional CD69(+)Qa2(-) CD4 single-positive thymocytes mature to the late CD69(-)Qa2(+) stage in the absence of RelB-dependent medullary thymic epithelial cells (mTECs). Furthermore, an increasing ability to continue maturation extrathymically is observed within the CD69(+)CCR7(-/lo)CCR9(+) subset of conventional SP4 thymocytes, providing evidence for an independence from medullary support by the earliest stages after positive selection. In contrast, Foxp3(+) nTreg cell development is medullary dependent, with mTECs fostering the generation of Foxp3(-)CD25(+) nTreg cell precursors at the CD69(+)CCR7(+)CCR9(-) stage. Our results demonstrate a differential requirement for the thymic medulla in relation to CD4 conventional and Foxp3(+) thymocyte lineages, in which an intact mTEC compartment is a prerequisite for Foxp3(+) nTreg cell development through the generation of Foxp3(-)CD25(+) nTreg cell precursors.
胸腺髓质的一个关键作用是负选择自身反应性的 CD4(+)和 CD8(+)胸腺细胞，这是诱导 T 细胞耐受的一个重要过程。然而，胸腺髓质在其他方面的 αβ T 细胞发育中的作用尚不清楚，包括 Foxp3(+)天然调节性 T 细胞（nTreg 细胞）的产生和阳性选择的常规 αβ T 细胞的持续成熟。我们发现，在没有 RelB 依赖性髓质胸腺上皮细胞（mTEC）的情况下，新生成的常规 CD69(+)Qa2(-)CD4 单阳性胸腺细胞成熟为晚期 CD69(-)Qa2(+)阶段。此外，在常规 SP4 胸腺细胞的 CD69(+)CCR7(-/lo)CCR9(+)亚群中，观察到在外周继续成熟的能力逐渐增强，为阳性选择后最早阶段的髓质支持独立性提供了证据。相比之下，Foxp3(+)nTreg 细胞的发育依赖于髓质，mTEC 促进了 Foxp3(-)CD25(+)nTreg 细胞前体在 CD69(+)CCR7(+)CCR9(-)阶段的产生。我们的结果表明，胸腺髓质与 CD4 常规和 Foxp3(+)胸腺细胞谱系的需求存在差异，其中完整的 mTEC 区室是通过产生 Foxp3(-)CD25(+)nTreg 细胞前体来发育 Foxp3(+)nTreg 细胞的先决条件。
