NKG2D recognition mediates Toll-like receptor 3 signaling-induced breakdown of epithelial homeostasis in the small intestines of mice.
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.
Zhou
Rongbin
R
Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei 230027, China.
Wei
Haiming
H
Sun
Rui
R
Zhang
Jian
J
Tian
Zhigang
Z
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis; D019409:Interleukin-15 / Q000494:pharmacology; D007421:Intestine, Small / Q000293:injuries / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000235:genetics; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D019409:Interleukin-15; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; D012330:RNA, Double-Stranded; C490521:Rae1 protein, mouse; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D051196:Toll-Like Receptor 3; D011070:Poly I-C