Intestinal epithelial cells (IECs) act as a physical barrier separating the commensal-containing intestinal tract from the sterile interior. These cells have found a complex balance allowing them to be prepared for pathogen attacks while still tolerating the presence of bacterial or viral stimuli present in the lumen of the gut. Using primary human IECs, we probed the mechanisms that allow for such a tolerance. We discovered that viral infections emanating from the basolateral side of IECs elicit a stronger intrinsic immune response in comparison to lumenal apical infections. We determined that this asymmetric immune response is driven by the clathrin-sorting adaptor AP-1B, which mediates the polarized sorting of Toll-like receptor 3 (TLR3) towards the basolateral side of IECs. Mice and human IECs lacking AP-1B showed an exacerbated immune response following apical stimulation. Together, these results suggest a model where the cellular polarity program plays an integral role in the ability of IECs to partially tolerate apical commensals while remaining fully responsive to invasive basolateral pathogens.

中文翻译：

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TLR3的不对称分布导致人肠上皮细胞极化免疫反应。

肠上皮细胞（IEC）充当物理屏障，将包含共生肠的肠道与无菌内部分隔开来。这些细胞已经发现了复杂的平衡，可以为病原体攻击做好准备，同时仍能耐受肠道内腔中细菌或病毒刺激物的存在。使用主要的人类IEC，我们探究了允许这种公差的机制。我们发现，与腔内顶端感染相比，从IECs的基底外侧发出的病毒感染引起了更强的内在免疫反应。我们确定这种不对称的免疫应答是由网格蛋白分选适配器AP-1B驱动的，该适配器介导Toll样受体3（TLR3）向IEC基底外侧的极化分选。缺乏AP-1B的小鼠和人类IECs在根尖刺激后显示出加剧的免疫反应。在一起，这些结果提出了一个模型，其中细胞极性程序在IECs耐受部分根尖菌的能力中起着不可或缺的作用，同时又保持对浸润性基底外侧病原体的完全反应。