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

doi:10.1073/pnas.0700822104

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

*Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale and School of Life of Sciences, University of Science and Technology of China, Hefei 230027, China; and
^†Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China

Edited by Tak Wah Mak, The Campbell Family Institute for Breast Cancer Research, Toronto, ON, Canada, and approved March 1, 2007 (received for review January 29, 2007)

Abstract

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 CD8αα 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.

Footnotes

^‡To whom correspondence should be addressed. E-mail: tzg{at}ustc.edu.cn
Author contributions: R.Z., H.W., R.S., and J.Z. designed research; R.Z. performed research; R.Z. analyzed data; and R.Z. and Z.T. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Abbreviations:

poly(I:C),

polyinosinic–polycytidylic acid;

IEL,

intestinal intraepithelial lymphocyte;

IEC,

intestinal epithelial cell;

TLR,

Toll-like receptor.