Oral probiotic promotes indoleamine 2,3-dioxygenase- and TGF-β-Producing plasmacytoid dendritic cells to initiate protection against type 1 diabetes.
Oral probiotic promotes indoleamine 2,3-dioxygenase- and TGF-β-Producing plasmacytoid dendritic cells to initiate protection against type 1 diabetes.
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DOI：
10.1016/j.imlet.2021.07.009
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发表时间：
2021-11
影响因子：
4.4
通讯作者：
Pascual, David W.
中科院分区：
文献类型：
--
作者：
Nelson, Andrew S.;Akgul, Ali;Maddaloni, Massimo;Bhagyaraj, Ella;Hoffman, Carol;Pascual, David W.
定植因子抗原I（CFA/I）菌毛，一种来自肠源性大肠杆菌的粘附素，在1型糖尿病（T1 D）、多发性硬化症和类风湿性关节炎的小鼠自身免疫模型中提供保护。虽然CFA/I菌毛的初始作用模式是旁观者或抗原（Ag）非依赖性方式，但保护最终依赖于自身Ag特异性调节性T细胞（Tcells）的诱导和/或活化。然而，很少有人知道如何从旁观者抑制的保护过渡到银特异性Tclase。由于树突状细胞（DC）在T细胞成为炎性或致耐受性的命运决定中起着不可或缺的作用，所描述的研究测试了表达CFA/I的乳酸乳球菌（LL-CFA/I）刺激DC建立调节微环境的假设。为此，在体外用LL-CFA/I感染骨髓来源的树突状细胞（BMDC）。结果显示IL-10、TGF-β和吲哚胺2，3-脱氧酶（IDO）的产生增加。尽管LL-CFA/I感染的BMDCs与初始T细胞共培养不能促进Foxp 3表达，但TNF-α和IFN-γ的产生受到抑制。经口给予LL-CFA/I的NOD小鼠在治疗后三天显示胰腺淋巴结（PaLN）和脾脏中表达IDO和TGF-β的调节性浆细胞样DC（pDC）增加。然而，TdR直到很久以后才出现在粘膜诱导部位。这些发现表明LL-CFA/I影响特定DC群体以建立耐受性。
Colonization factor antigen I (CFA/I) fimbria, an adhesin from enterotoxigenic Escherichia coli, confers protection in murine autoimmune models for type 1 diabetes (T1D), multiple sclerosis, and rheumatoid arthritis. Although CFA/I fimbriae’s initial mode of action is in a bystander or in an antigen (Ag)-independent fashion, protection is ultimately dependent upon the induction and/or activation of auto-Ag-specific regulatory T cells (Tregs). However, little is known about how protection transitions from bystander suppression to Ag-specific Tregs. Since dendritic cells (DCs) play an integral role in fate decisions for T cells becoming inflammatory or tolerogenic, the described study tests the hypothesis that Lactococcus lactis expressing CFA/I (LL-CFA/I) stimulates DCs to establish a regulatory microenvironment. To this end, bone marrow-derived dendritic cells (BMDCs) were infected in vitro with LL-CFA/I. Results revealed increased production of IL-10, TGF-β, and indoleamine 2,3-deoxygenase (IDO). Although co-culture of LL-CFA/I infected BMDCs with naïve T cells did not promote Foxp3 expression, TNF-α and IFN-γ production was suppressed. NOD mice orally dosed with LL-CFA/I showed an increase in regulatory plasmacytoid DCs (pDCs) expressing IDO and TGF-β in pancreatic lymph nodes (PaLNs) and spleen three days post-treatment. However, Tregs did not appear in the mucosal inductive sites until much later. These findings show that LL-CFA/I influences specific DC populations to establish tolerance.
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