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Recognition of Double-Stranded RNA by TLR3 Induces Severe Small Intestinal Injury in Mice¹

Hefei National Laboratory for Physical Sciences at Microscale and School of Life of Sciences’ University of Science and Technology of China, Hefei, China

The role of TLRs on intestinal epithelial cells (IECs) is controversial, and the mechanisms by which TLRs influence mucosal homeostasis are obscure. In this study, we report that genomic dsRNA from rotavirus, and its synthetic analog polyinosinic-polycytidylic acid (poly(I:C)), induce severe mucosal injury in the small intestine. Upon engaging TLR3 on IECs, dsRNA triggers IECs to secrete IL-15, which functions to increase the percentage of CD3⁺NK1.1⁺ intestinal intraepithelial lymphocytes (IELs) and enhances the cytotoxicity of IELs. Moreover, The CD3⁺NK1.1⁺ IELs are proved as CD8⁺ IELs. These results provide direct evidence that abnormal TLR3 signaling contributes to breaking down mucosal homeostasis and the first evidence of pathogenic effects mediated by CD8⁺ IELs. The data also suggest that genomic dsRNA may be involved in the pathogenesis of acute rotavirus gastroenteritis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by the National Natural Science Foundation of China (30630059, 30528007, 30570819, 30571695, and 30500467) and Grant from Ministry of Education of Peoples’ Republic of China (705029).

² R.Z. and H.W. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Zhigang Tian, School of Life Sciences, University of Science and Technology of China, 443 Huang-shan Road, Hefei, China. E-mail address: tzg{at}ustc.edu.cn

⁴ Abbreviations used in this paper: IEL, intestinal intraepithelial lymphocyte; CD, celiac disease; ECM, epithelial cell medium; IEC, intestinal epithelial cell; LPL, lamina-propria lymphocyte; LTA, lipoteichoic acid; PKR, protein kinase R; poly(I:C), polyinosinic-polycytidylic; rh, recombinant human; RQ, relative quantity; RV, rotavirus.

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