TSCOT+ thymic epithelial cell-mediated sensitive CD4 tolerance by direct presentation
TSCOT+ thymic epithelial cell-mediated sensitive CD4 tolerance by direct presentation
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DOI：
10.1371/journal.pbio.0060191
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发表时间：
2008-08-01
期刊：
影响因子：
9.8
通讯作者：
Kim, Moon Gyo
中科院分区：
文献类型：
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作者：
Ahn, Sejin;Lee, Gwanghee;Kim, Moon Gyo
尽管人们在剖析中枢耐受机制方面付出了很多努力，但胸腺基质细胞的作用仍然难以捉摸。为了进一步表征这一事件，我们开发了一种将 LacZ 限制于表达胸腺基质协同转运蛋白 (TSCOT) 的胸腺基质细胞 (TDLacZ) 的小鼠模型。该小鼠的胸腺含有大约 4,300 个 TSCOT+ 细胞，每个细胞表达数千个 LacZ 抗原分子。 TSCOT+ 细胞表达皮质标记物 CDR1、CD40、CD80、CD54 和主要组织相容性复合体 II 类 (MHCII)。当检查针对 LacZ 的内源性反应时，我们观察到显着的耐受性。通过 CD4 T 细胞增殖测定和抗原特异性抗体同种型分析测量的多样化 T 细胞库证明了这一点。这种耐受过程至少部分独立于自身免疫调节元件基因表达。当 TDLacZ 小鼠与一种针对 LacZ (BgII) 具有反应性的新型 CD4 T 细胞受体 (TCR) 转基因小鼠杂交时，双阳性胸腺细胞完全缺失。来自 TDLacZ 和分选的 TCR 胸腺细胞的 CD45 和 UEA 耗尽的胸腺基质细胞的胎儿胸腺重新聚集培养物排除了胸腺树突状细胞和髓质上皮细胞交叉呈递的可能性。总体而言，这些结果表明，将新抗原引入 TSCOT 表达细胞可以有效地建立完全耐受性，并表明通过将抗原引入 TSCOT+ 细胞来删除抗原特异性 T 细胞的可能应用。
Although much effort has been directed at dissecting the mechanisms of central tolerance, the role of thymic stromal cells remains elusive. In order to further characterize this event, we developed a mouse model restricting LacZ to thymic stromal cotransporter (TSCOT)-expressing thymic stromal cells (TDLacZ). The thymus of this mouse contains approximately 4,300 TSCOT+ cells, each expressing several thousand molecules of the LacZ antigen. TSCOT+ cells express the cortical marker CDR1, CD40, CD80, CD54, and major histocompatibility complex class II (MHCII). When examining endogenous responses directed against LacZ, we observed significant tolerance. This was evidenced in a diverse T cell repertoire as measured by both a CD4 T cell proliferation assay and an antigen-specific antibody isotype analysis. This tolerance process was at least partially independent of Autoimmune Regulatory Element gene expression. When TDLacZ mice were crossed to a novel CD4 T cell receptor (TCR) transgenic reactive against LacZ (BgII), there was a complete deletion of double-positive thymocytes. Fetal thymic reaggregate culture of CD45-and UEA-depleted thymic stromal cells from TDLacZ and sorted TCR-bearing thymocytes excluded the possibility of cross presentation by thymic dendritic cells and medullary epithelial cells for the deletion. Overall, these results demonstrate that the introduction of a neoantigen into TSCOT-expressing cells can efficiently establish complete tolerance and suggest a possible application for the deletion of antigen-specific T cells by antigen introduction into TSCOT+ cells.