Murine lupus susceptibility locus Slela controls regulatory T cell number and function through multiple mechanisms
Murine lupus susceptibility locus Slela controls regulatory T cell number and function through multiple mechanisms
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DOI：
10.4049/jimmunol.179.11.7439
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发表时间：
2007-12-01
影响因子：
4.4
通讯作者：
Morel, Laurence
中科院分区：
文献类型：
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作者：
Cuda, Carla M.;Wan, Suigui;Morel, Laurence
Sel基因座是NZM 2410小鼠模型中狼疮易感性的关键决定因素。在Slel中，我们先前已经表明Slela表达增强了CD 4（+）T细胞的活化水平和效应子功能，并减少了CD 4（+）CD 25（+）Foxp 3（+）调节性T细胞亚群的大小，导致产生为染色质特异性B细胞提供帮助的自身反应性T细胞。在这项研究中，我们发现Slela CD 4（+）T细胞表达高水平的ICOS，这与它们帮助自身反应性B细胞的能力增加一致。此外，Slela CD 4（+）CD 25（+）T细胞表达低水平的Foxp 3。混合骨髓嵌合体表明，这些表型需要Slela在受影响的CD 4（+）T细胞中表达。与Foxp 3（+）细胞中的Slela表达无关，通常与调节性T细胞（T细胞）相关的其他标志物的表达是相似的。沿着体外和体内抑制研究的这一结果表明，Slela控制的是T细胞的数量，而不是它们在每个细胞基础上的功能。体外和体内抑制测定也显示Slela表达诱导效应T细胞对Treg抑制具有抗性，以及树突状细胞过度产生抑制Treg抑制的IL-6。总体而言，这些结果表明，Slela通过多种机制控制Treg数量和功能，直接作用于Treg本身，间接通过效应T细胞的应答和树突状细胞的调节作用。
The Slel locus is a key determinant of lupus susceptibility in the NZM2410 mouse model. Within Slel, we have previously shown that Slela expression enhances activation levels and effector functions of CD4(+) T cells and reduces the size of the CD4(+) CD25(+)Foxp3(+) regulatory T cell subset, leading to the production of autoreactive T cells that provide help to chromatin-specific B cells. In this study, we show that Slela CD4(+) T cells express high levels of ICOS, which is consistent with their increased ability to help autoreactive B cells. Furthermore, Slela CD4(+)CD25(+) T cells express low levels of Foxp3. Mixed bone marrow chimeras demonstrated that these phenotypes require Slela to be expressed in the affected CD4(+) T cells. Expression of other markers generally associated with regulatory T cells (Tregs) was similar regardless of Slela expression in Foxp3(+) cells. This result, along with in vitro and in vivo suppression studies, suggests that Slela controls the number of Tregs rather than their function on a per cell basis. Both in vitro and in vivo suppression assays also showed that Slela expression induced effector T cells to be resistant to Treg suppression, as well as dendritic cells to overproduce IL-6, which inhibits Treg suppression. Overall, these results show that Slela controls both Treg number and function by multiple mechanisms, directly on the Tregs themselves and indirectly through the response of effector T cells and the regulatory role of dendritic cells.