Deficiency of the Src homology region 2 domain-containing phosphatase 1 (SHP-1) causes enrichment of CD4+CD25+ regulatory T cells
Deficiency of the Src homology region 2 domain-containing phosphatase 1 (SHP-1) causes enrichment of CD4+CD25+ regulatory T cells
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DOI：
10.4049/jimmunol.174.11.6627
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发表时间：
2005-06-01
影响因子：
4.4
通讯作者：
Lorenz, U
中科院分区：
文献类型：
--
作者：
Carter, JD;Calabrese, GM;Lorenz, U
T细胞的一个亚群，被称为调节性T细胞(T-reg细胞)，已被证明在耐受和预防自身免疫中发挥关键作用。目前尚不清楚胸腺T细胞发育过程中TCR信号强度的变化如何影响T-reg群体的产生。在这项研究中，我们采取了两种不同的策略来调节TCR信号强度：一种是内源性方法，通过失去负调控因子来增强信号强度；另一种是外源性方法，即通过改变选择多肽的浓度来改变信号强度。酪氨酸磷酸酶Src同源区2含结构域的磷酸酶1(SHP-1)是一种已知的TCR介导的信号负调控因子。在缺乏SHP-1表达的小鼠中，CD4(+)CD25(+)T-reg细胞占CD4(+)T细胞的百分比增加了2~3倍。同样，从母鼠胎胸腺器官培养(FTOCs)中T-reg细胞的比例高于野生型FTOCs，从而确立了这些Treg细胞的胸腺来源。使用来自DO11.10 TCR转基因小鼠的FTOCs，我们证明了暴露于浓度增加的同源OVA肽有利于T-reg细胞的出现。我们的数据表明，CD4(+)CD25(+)T-reg细胞的发育本质上不同于非T-reg细胞，在增强的阴性选择条件下，T-reg细胞被选择性地浓缩。我们的数据还揭示了SHP-1介导的TCR信号强度调节在影响Treg与非T-reg细胞比率中的关键作用。
A subpopulation of T cells, named regulatory T cells (T-reg cells), has been shown to play a key role in tolerance and the prevention of autoimmunity. It is not known how changes in TCR signal strength during thymic T cell development affect the generation of a T-reg population. In this study, we took two different strategies to modulate the TCR signal strength: an intrinsic approach, where signaling was enhanced by the loss of a negative regulator, and an extrinsic approach, where signaling strength was altered through variations in the concentrations of the selecting peptide. The tyrosine phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP-1) is a known negative regulator of TCR-mediated signaling. motheaten mice, lacking expression of SHP-1, showed a 2- to 3-fold increase in the percentage of CD4(+)CD25(+) T-reg cells within the CD4(+) T cells. Similarly, the percentage of T-reg cells was heightened in fetal thymic organ cultures (FTOCs) derived from motheaten mice compared with wild-type FTOCs, thus establishing the thymic origin of these Treg cells. Using FTOCs derived from DO11.10 TCR transgenic mice, we demonstrated that exposure to increasing concentrations of the cognate OVA peptide favored the appearance of T-reg cells. Our data suggest that the development of CD4(+)CD25(+) T-reg cells is intrinsically different from non-T-reg cells and that T-reg cells are selectively enriched under conditions of enhanced negative selection. Our data also reveal a key role for the SHP-1-mediated regulation of TCR signal strength in influencing the ratio of Treg vs non-T-reg cells.