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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The Defect In T-cell Regulation In Nod Mice Is An Effect On The T-cell Effectors
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The Defect In T-cell Regulation In Nod Mice Is An Effect On The T-cell Effectors

机译：Nod小鼠T细胞调节的缺陷是对T细​​胞效应子的影响

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FoxP3~+ regulatory T cells (Tregs) protect against autoimmunity, type 1 diabetes (T1D) in particular, prompting the hypothesis that a deficiency in Tregs is a critical determinant of diabetes susceptibility in NOD mice. However, tests of this hypothesis have yielded contradictory results. We confirmed that NOD mice, compared with reference strains, do not have a primary deficit in Treg numbers in the lymphoid organs, whether in prediabetic mice of any age or in animals with recent-onset diabetes. NOD Tregs did show a defect in standard in vitro T cell suppression assays, particularly at low suppressor/effector ratios. Gene expression profiling revealed the vast majority of transcripts constituting the "Treg signature" to be normally distributed in NOD Tregs versus CD4~+ T conventional (Tconv) cells, although there were a few differences affecting one or the other population. According to results from criss-cross experiments, the functional inefficacy was not rooted in NOD Tregs, which suppressed as well as their C57BL/6 (B6) counterparts, but rather in NOD Tconv, which were less prone to suppression than were B6 Tconv cells. They also responded more effectively to anti-CD3/28 monoclonal antibody (mAb) stimulation in vitro or to a natural pancreatic antigen in vivo. This difference was independent of autoimmune inflammation, did not map to the idd3 region, and was not due to the overproduction of interleukin-21 in NOD mice. That the immune dysregulation in this T1D model is rooted in the ability of effector T cells to be regulated, rather than in Tregs themselves, has implications for proposed therapeutic interventions.
机译：FoxP3〜+调节性T细胞（Tregs）可以抵抗自身免疫，特别是1型糖尿病（T1D），这提示了Tregs缺乏是NOD小鼠糖尿病易感性的关键决定因素。但是，对该假设的检验得出了矛盾的结果。我们证实，与参考菌株相比，无论在任何年龄的糖尿病前期小鼠还是新近发病的糖尿病动物中，NOD小鼠在淋巴器官中的Treg数量均没有主要的缺陷。 NOD Tregs在标准的体外T细胞抑制试验中确实显示出缺陷，特别是在低抑制剂/效应物比率下。基因表达谱分析显示，构成“ Treg标记”的绝大多数转录本相对于CD4〜+ T常规（Tconv）细胞通常分布在NOD Tregs中，尽管影响一个或另一个群体的差异很小。根据交叉实验的结果，功能低下不是根源于NOD Treg及其抑制的C57BL / 6（B6）对应物，而是根源于NOD Tconv，后者比B6 Tconv细胞更不容易被抑制。他们还更有效地响应了体外抗CD3 / 28单克隆抗体（mAb）的刺激或体内对天然胰腺抗原的刺激。这种差异与自身免疫炎症无关，没有映射到idd3区域，并且不是由于NOD小鼠中白介素21的过量产生。这种T1D模型中的免疫失调是由于调节效应T细胞的能力而不是Treg本身而引起的，这对建议的治疗干预具有影响。

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