Thymocyte dynamics and hymus organogenesis

T淋巴细胞在维持免疫监视中起着关键作用。胸腺中产生T淋巴细胞，胸腺发育中的T淋巴细胞通过正负选择过程获得对外来抗原的反应性，并建立对自身抗原的耐受。然而，T淋巴细胞是如何在胸腺微环境中产生和选择的，目前仍知之甚少。本研究的目的是了解形成具有功能的胸腺的分子程序，该胸腺能够支持和选择T淋巴细胞，并定位于发育中的T淋巴细胞定位于多种胸腺微环境中，以集中形成T淋巴细胞库。我们发现，CCR7和CCR9介导的趋化因子信号之间的时空协调对T祖细胞在胎儿胸腺的血管前定植起着关键的调节作用。我们还发现，CCR7介导的趋化因子信号对于发育中的胸腺细胞从皮质到髓质的迁移是必不可少的，而依赖CCR7的胸腺细胞从皮质到髓质的迁移对于建立对组织限制性抗原的中枢耐受是必不可少的。此外，通过使用在未成熟淋巴细胞特异性RAG1控制下表达荧光蛋白的转基因青海(一种透明的小鱼)，建立了无需手术入侵的活体内胸腺细胞的实时成像。最后，对化学诱变的青竹进行全基因组筛选，确定了至少22个对胸腺形成起关键调节作用的基因。揭示对建立有功能的胸腺和胸腺内T淋巴细胞选择至关重要的分子机制应该有助于控制免疫疾病。

T lymphocytes play a pivotal role in maintaining immunological surveillance. T lymphocytes are generated in the thymus, and it is well established that developing T lymphocytes in the thymus acquire the reactivity to foreign antigens and establish tolerance to self-antigens through the process of positive and negative selection. However, how T lymphocytes are generated and selected in thymus microenvironments is still poorly understood. This study was aimed to understand molecular programs that form functionally competent thymus, which is capable of supporting and selecting T lymphocytes, and that position developing T lymphocytes to localize within multiple thymic microenvironments for centrally shaping T-lymphocyte repertoire. We found that spatial and temporal coordination between CCR7-and CCR9-mediated chemokine signals critically regulates pre-vascular colonization of T-progenitor cells into fetal thymus. We also found that CCR7-mediated chemokine signals are essential for cortex-to-medulla migration of developing thymocytes, and that CCR7-dependent cortex-to-medulla migration of positively selected thymocytes is essential for establishing central tolerance to tissue-restricted antigens. Moreover, real-time imaging of intra-vital thymocytes without surgical invasion was established by using transgenic medaka (a transparent small fish species) that expresses fluorescent protein under the control of immature-lymphocyte-specific rag1. Finally, genome-wide screening of chemically mutagenized medaka identified at least 22 genes that critically regulate the formation of the thymus. Unveiling molecular machinery that is essential for establishing functional thymus and intra-thymic T lymphocyte selection should aid controlling immune diseases.