The countervailing actions of myeloid and plasmacytoid dendritic cells control autoimmune diabetes in the nonobese diabetic mouse
The countervailing actions of myeloid and plasmacytoid dendritic cells control autoimmune diabetes in the nonobese diabetic mouse
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DOI：
10.4049/jimmunol.179.8.5041
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发表时间：
2007-10-15
影响因子：
4.4
通讯作者：
Katz, Jonathan D.
中科院分区：
文献类型：
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作者：
Saxena, Vijay;Ondr, Jennifer K.;Katz, Jonathan D.
胰岛ag特异性CD4(+) T细胞接受MHC类h表达apc的抗原刺激。在这里，我们通过白喉毒素介导的细胞消融，描述了NOD小鼠1型糖尿病中巨噬细胞和树突状细胞（DC）不同亚群的直接体内必要性。在转移或自发模型中，巨噬细胞消融对胰岛Ag呈递或诱导胰岛素或糖尿病没有影响。然而，CD11b(+)CD11c(+) DC的消融导致T细胞活化丧失，由CD4(+) T细胞介导的胰岛素和糖尿病。当特定的髓系DC亚群被“加回”到缺乏全部DC的小鼠时，胰岛素和糖尿病恢复。有趣的是，当NOD小鼠进入胰岛素期时，DC的消融导致胰岛素加速。这种加速的胰岛素炎是由浆细胞样DC （pDC）的丧失介导的。当pDC返回衰竭小鼠时，恢复了胰岛素的局部调节。胰腺自身pDC的丢失伴随着局部IDO的丢失和胰岛素炎的加速。因此，CD11c(+)CD11b(+) DC和pDC在NOD糖尿病中具有抵消作用，髓性DC为初始CD4(+) T细胞提供关键的抗原刺激，而pDC在靶组织中对CD4(+) T细胞功能进行调节控制。
Islet Ag-specific CD4(+) T cells receive antigenic stimulation from MHC class H-expressing APCs. Herein, we delineate the direct in vivo necessity for distinct subsets of macrophages and dendritic cells (DC) in type 1 diabetes mellitus of the NOD mouse by using diphtheria toxin-mediated cell ablation. The ablation of macrophages had no impact on islet Ag presentation or on the induction of insulitis or diabetes in either transfer or spontaneous models. However, the ablation of CD11b(+)CD11c(+) DC led to the loss of T cell activation, insulitis, and diabetes mediated by CD4(+) T cells. When the specific myeloid DC subset was "added-back" to mice lacking total DC, insulitis and diabetes were restored. Interestingly, when NOD mice were allowed to progress to the insulitis phase, the ablation of DC led to accelerated insulitis. This accelerated insulitis was mediated by the loss of plasmacytoid DC (pDC). When pDC were returned to depleted mice, the localized regulation of insulitis was restored. The loss of pDC in the pancreas itself was accompanied by the localized loss of IDO and the acceleration of insulitis. Thus, CD11c(+)CD11b(+) DC and pDC have countervailing actions in NOD diabetes, with myeloid DC providing critical antigenic stimulation to naive CD4(+) T cells and pDC providing regulatory control of CD4(+) T cell function in the target tissue.