Cooper Cristine J, Orr Mark T, McMahan Catherine J, Fink Pamela J
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
J Immunol. 2003 Jul 1;171(1):226-33. doi: 10.4049/jimmunol.171.1.226.
CD4(+)Vbeta5(+) T cells enter one of two tolerance pathways after recognizing a peripherally expressed superantigen encoded by an endogenous retrovirus. One pathway leads to deletion, while the other, termed TCR revision, results in cellular rescue upon expression of an alternate TCR that no longer recognizes the tolerogen. TCR revision requires the rearrangement of novel TCR beta-chain genes and depends on recombinase-activating gene (RAG) expression in peripheral T cells. In line with recent findings that RAG(+) splenic B cells are immature cells that have maintained RAG expression, it has been hypothesized that TCR revision is limited to recent thymic emigrants that have maintained RAG expression and TCR loci in a recombination-permissive configuration. Using mice in which the expression of green fluorescent protein is driven by the RAG2 promoter, we now show that in vitro stimulation can drive reporter expression in noncycling, mature, peripheral CD4(+) T cells. In addition, thymectomized Vbeta5 transgenic RAG reporter mice are used to demonstrate that TCR revision can target peripheral T cells up to 2 mo after thymectomy. Both sets of experiments strongly suggest that reinduction of RAG genes triggers TCR revision. Approximately 3% of CD4(+)Vbeta5(+) T cells in thymectomized Vbeta5 transgenic reporter mice have undergone TCR revision within the previous 4-5 days. TCR revision can also occur in Vbeta5(+) T cells from nontransgenic mice, illustrating the relevance of this novel tolerance mechanism in unmanipulated animals.
CD4(+)Vbeta5(+) T细胞在识别由内源性逆转录病毒编码的外周表达超抗原后，进入两条耐受途径之一。一条途径导致细胞凋亡，而另一条途径称为TCR重排，当表达不再识别耐受原的替代TCR时，会导致细胞存活。TCR重排需要新的TCRβ链基因重排，并依赖于外周T细胞中重组酶激活基因（RAG）的表达。与最近发现RAG(+)脾B细胞是维持RAG表达的未成熟细胞一致，有人推测TCR重排仅限于维持RAG表达且TCR基因座处于重组允许状态的近期胸腺迁出细胞。利用绿色荧光蛋白表达由RAG2启动子驱动的小鼠，我们现在表明体外刺激可在非循环、成熟的外周CD4(+) T细胞中驱动报告基因表达。此外，切除胸腺的Vbeta5转基因RAG报告小鼠用于证明TCR重排在胸腺切除后长达2个月可靶向外周T细胞。这两组实验都强烈表明RAG基因的重新诱导触发TCR重排。在切除胸腺的Vbeta5转基因报告小鼠中，约3%的CD4(+)Vbeta5(+) T细胞在过去4-5天内经历了TCR重排。TCR重排在非转基因小鼠的Vbeta5(+) T细胞中也可发生，这说明了这种新的耐受机制在未处理动物中的相关性。
