Treg发育研究新进展
丁香园论坛
1068
Nature Immunology 10, 610 - 617 (2009)
Intraclonal competition limits the fate determination of regulatory T cells in the thymus
Jhoanne L Bautista, Chan-Wang J Lio, Stephanie K Lathrop, et al.
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AbstractBecause the deletion of self-reactive T cells is incomplete, thymic development of natural Foxp3+CD4+ regulatory T cells (Treg cells) is required for preventing autoimmunity. However, the function of T cell antigen receptor (TCR) specificity in thymic Treg cell development remains controversial. To address this issue, we generated a transgenic line expressing a naturally occurring Treg cell–derived TCR. Unexpectedly, we found that efficient thymic Treg cell development occurred only when the antigen-specific Treg cell precursors were present at low clonal frequency (<1%) in a normal thymus. Using retroviral vectors and bone marrow chimeras, we observed similar activity with two other Treg cell–derived TCRs. Our data demonstrate that thymic Treg cell development is a 'TCR-instructive' process involving a niche that can be saturable at much lower clonal frequencies than is the niche for positive selection.
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内容简介：
TCR转基因鼠的诞生为T细胞发育，尤其是阳性和阴性选择研究提供了强大的模型。但是，由于特定TCR前体细胞在转基因鼠内的绝对优势表达，掩盖了T细胞的正常发育进程，因此TCR转基因鼠更多的被用于T细胞特定发育阶段的研究(阳性选择和阴性选择)。另外，转基因鼠模型内特定TCR过早和强化表达是否会影响特定T细胞亚群的发育进程，也是隐忧之处。
本文通过Treg TCR转基因鼠模型的研究，发现当转基因TCR阳性细胞达到总细胞量10%时，相应Foxp3阳性细胞含量为1%；反之，当转基因TCR阳性细胞占总量0.1%时，相应TCR阳性的Foxp3阳性细胞含量为30%。尽管随着转基因TCR阳性细胞含量减少，相应TCR阳性的Foxp3阳性细胞的比例不断增加，但是相应Foxp3阳性细胞数量却存在上限(10000细胞/鼠)——这表明转基因鼠体内存在相应的niche，限制Foxp3阳性Treg细胞的发育。
本文最大的亮点在于证实了TCR转基因鼠模型中，Treg细胞的数量并非随相应TCR阳性细胞数量(比例)增加而扩增，其发育存在niche限制性，从而引发Treg发育模式的思考：是否在Treg发育过程中，存在TCR-肽亲和力的选择性模式（见二楼 News and Views）?
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Intraclonal competition limits the fate determination of regulatory T cells in the thymus
Jhoanne L Bautista, Chan-Wang J Lio, Stephanie K Lathrop, et al.
--------------------------------------------------------------------------------
AbstractBecause the deletion of self-reactive T cells is incomplete, thymic development of natural Foxp3+CD4+ regulatory T cells (Treg cells) is required for preventing autoimmunity. However, the function of T cell antigen receptor (TCR) specificity in thymic Treg cell development remains controversial. To address this issue, we generated a transgenic line expressing a naturally occurring Treg cell–derived TCR. Unexpectedly, we found that efficient thymic Treg cell development occurred only when the antigen-specific Treg cell precursors were present at low clonal frequency (<1%) in a normal thymus. Using retroviral vectors and bone marrow chimeras, we observed similar activity with two other Treg cell–derived TCRs. Our data demonstrate that thymic Treg cell development is a 'TCR-instructive' process involving a niche that can be saturable at much lower clonal frequencies than is the niche for positive selection.
--------------------------------------------------------------------------------
内容简介：
TCR转基因鼠的诞生为T细胞发育，尤其是阳性和阴性选择研究提供了强大的模型。但是，由于特定TCR前体细胞在转基因鼠内的绝对优势表达，掩盖了T细胞的正常发育进程，因此TCR转基因鼠更多的被用于T细胞特定发育阶段的研究(阳性选择和阴性选择)。另外，转基因鼠模型内特定TCR过早和强化表达是否会影响特定T细胞亚群的发育进程，也是隐忧之处。
本文通过Treg TCR转基因鼠模型的研究，发现当转基因TCR阳性细胞达到总细胞量10%时，相应Foxp3阳性细胞含量为1%；反之，当转基因TCR阳性细胞占总量0.1%时，相应TCR阳性的Foxp3阳性细胞含量为30%。尽管随着转基因TCR阳性细胞含量减少，相应TCR阳性的Foxp3阳性细胞的比例不断增加，但是相应Foxp3阳性细胞数量却存在上限(10000细胞/鼠)——这表明转基因鼠体内存在相应的niche，限制Foxp3阳性Treg细胞的发育。
本文最大的亮点在于证实了TCR转基因鼠模型中，Treg细胞的数量并非随相应TCR阳性细胞数量(比例)增加而扩增，其发育存在niche限制性，从而引发Treg发育模式的思考：是否在Treg发育过程中，存在TCR-肽亲和力的选择性模式（见二楼 News and Views）?
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