CiteULike: AlfonsoVicenteSuarez's Zhou

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

Rongbin Zhou — 2008-05-27T18:31:42-00:00

J Immunol, Vol. 178, No. 7. (1 April 2007), pp. 4548-4556.

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 CD8alphaalpha+ 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 CD8alphaalpha+ IELs. The data also suggest that genomic dsRNA may be involved in the pathogenesis of acute rotavirus gastroenteritis.

NKG2D recognition mediates Toll-like receptor 3 signaling-induced breakdown of epithelial homeostasis in the small intestines of mice

Rongbin Zhou — 2008-05-25T05:03:00-00:00

Proceedings of the National Academy of Sciences, Vol. 104, No. 18. (1 May 2007), pp. 7512-7515.

Toll-like receptors (TLRs) and NK receptors are the two most important receptor families in innate immunity. Although it has been observed that TLR signaling can induce or up-regulate the expression of the ligands for stimulatory NK receptors on monocytes or muscle cells, there is not yet a report indicating whether TLR signaling can break down self-tolerance through NK receptors. The present work reports that TLR3 signaling by polyinosinic-polycytidylic acid stimulation induces intestinal epithelial cells (IECs) to express retinoic acid early inducible-1 (a ligand for NKG2D) and to induce NKG2D expression on CD8alphaalpha intestinal intraepithelial lymphocytes by IL-15 derived from TLR3-activated IECs. The blockade of interaction between NKG2D and Rae1 inhibits the cytotoxicity of intraepithelial lymphocytes against IECs in a cell-cell contact-dependent manner and therefore alleviates polyinosinic-polycytidylic acid-induced epithelial destruction and acute mucosal injury of small intestine. These results demonstrate that TLR signaling induces tissue injury through the NKG2D pathway, suggesting that TLR signaling may break down self-tolerance through induction of abnormal expression of ligands for stimulatory NK receptors. 10.1073/pnas.0700822104

DNA-based vaccines activate innate and adaptive antitumor immunity by engaging the NKG2D receptor

He Zhou — 2008-05-09T23:48:55-00:00

Proceedings of the National Academy of Sciences, Vol. 102, No. 31. (2 August 2005), pp. 10846-10851.

The interaction of NKG2D, a stimulatory receptor expressed on natural killer (NK) cells and activated CD8+ T cells, and its ligands mediates stimulatory and costimulatory signals to these cells. Here, we demonstrate that DNA-based vaccines, encoding syngeneic or allogeneic NKG2D ligands together with tumor antigens such as survivin or carcinoembryonic antigen, markedly activate both innate and adaptive antitumor immunity. Such vaccines result in highly effective, NK- and CD8+ T cell-mediated protection against either breast or colon carcinoma cells in prophylactic and therapeutic settings. Notably, this protection was irrespective of the NKG2D ligand expression level of the tumor cells. Hence, this strategy has the potential to lead to widely applicable and possibly clinically useful DNA-based cancer vaccines. 10.1073/pnas.0502208102