The Hedgehog Receptor Patched1 in T Cells Is Dispensable for Adaptive Immunity in Mice
The Hedgehog Receptor Patched1 in T Cells Is Dispensable for Adaptive Immunity in Mice
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DOI：
10.1371/journal.pone.0061034
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发表时间：
2013-04-08
期刊：
影响因子：
3.7
通讯作者：
Reichardt, Holger M.
中科院分区：
文献类型：
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作者：
Michel, Kai D.;Uhmann, Anja;Reichardt, Holger M.
Hedgehog （Hh）信号调节T细胞的发育和功能，但其确切作用仍存在争议。为了进一步解决这个问题，我们使用条件敲除小鼠，其中Hh受体Patched1 （Ptch）在T细胞谱系中失活。胸腺细胞发育受到Ptch缺失的中度损害，其特征是CD4和CD8单阳性细胞数量减少。相反，外周T细胞不受影响。无论我们使用强刺激还是次优刺激条件，ptch缺陷T细胞的增殖和IFN γ分泌与对照组没有区别。CTL和T-reg细胞功能分析显示两种基因型之间没有任何差异，糖皮质激素或γ辐照诱导的T细胞凋亡也相似。令人惊讶的是，Ptch的缺失并没有导致外周T细胞中经典Hh信号的激活，Gli1和Gli2的表达水平不变表明了这一点。为了测试我们是否可以在体内发现Ptch在T细胞中的任何作用，我们对突变小鼠进行了三种不同的疾病模型，即模拟移植物抗宿主病的同种异体骨髓移植，过敏性气道炎症作为哮喘模型，以及过继性转移黑色素瘤细胞的生长作为测试免疫系统肿瘤监测的手段。然而，我们既不能证明这三种适应性免疫模型在病程和任何致病参数上有任何差异。因此，我们得出结论，无论在体内还是体外，Hh受体Ptch对于T细胞的功能都是必不可少的。
Hedgehog (Hh) signaling modulates T cell development and function but its exact role remains a matter of debate. To further address this issue we made use of conditional knock-out mice in which the Hh receptor Patched1 (Ptch) is inactivated in the T cell lineage. Thymocyte development was moderately compromised by the deletion of Ptch as characterized by reduced numbers of CD4 and CD8 single-positive cells. In contrast, peripheral T cells were not affected. Proliferation and IFN gamma secretion by Ptch-deficient T cells were indistinguishable from controls irrespectively of whether we used strong or suboptimal conditions for stimulation. Analysis of CTL and T-reg cell functions did not reveal any differences between both genotypes, and T cell apoptosis induced by glucocorticoids or gamma-irradiation was also similar. Surprisingly, absence of Ptch did not lead to an activation of canonic Hh signaling in peripheral T cells as indicated by unaltered expression levels of Gli1 and Gli2. To test whether we could uncover any role of Ptch in T cells in vivo we subjected the mutant mice to three different disease models, namely allogeneic bone marrow transplantation mimicking graft-versus-host disease, allergic airway inflammation as a model of asthma and growth of adoptively transferred melanoma cells as a means to test tumor surveillance by the immune system. Nonetheless, we were neither able to demonstrate any difference in the disease courses nor in any pathogenic parameter in these three models of adaptive immunity. We therefore conclude that the Hh receptor Ptch is dispensable for T cell function in vitro as well as in vivo.