CD200R is an inhibitory receptor expressed on myeloid cells and some lymphoid cells and plays important roles in negatively regulating immune responses. and cytolytic activity by activated IELs. Thus iSEC1 is a previously unappreciated CD200R ligand with restricted expression in gastrointestinal secretory cells and may negatively regulate mucosal immune responses. Paired receptors are closely related membrane proteins that share similar extracellular regions but have distinct transmembrane and cytoplasmic regions NSC697923 and regulate immune responses by transducing opposing signals either inhibitory or activating upon ligand binding1 2 The CD200R family is one of paired receptor families and consists of five members in mice one inhibitory receptor (CD200R) and four CD200R-like receptors with activating activity (termed either CD200R2-5 or CD200RLa-e)3 4 5 6 7 8 9 10 CD200 is the only known ligand of the CD200R family and has been shown to bind to CD200R but no other members4 7 11 CD200 is broadly distributed in a variety of cell types including non-hematopoietic cells whereas CD200R is primarily expressed in myeloid and lymphoid cells6 12 Both CD200 and CD200R contain two extracellular immunoglobulin superfamily (IgSF) domains and a single-pass transmembrane region and interact with each other through their N-terminal IgSF domains13. The CD200R intracellular domain lacks the typical immunoreceptor tyrosine-based inhibitory motif (ITIM) present in most immune inhibitory receptors but it contains three tyrosine residues that can be phosphorylated and contribute to inhibitory signaling14. Recent studies including analyses with CD200R- or NSC697923 CD200-deficient mice have demonstrated that the CD200-CD200R interaction plays important roles in negatively regulating immune responses and attenuate autoimmune diseases excessive inflammatory responses against pathogens or anti-tumor immunity9 15 16 17 18 19 20 Functional roles of CD200R-like receptors have been ill-defined compared to those of CD200R. Among four members CD200R3 (CD200RLb) is unique in terms of structure and expression. It exists as a disulfide-linked homodimer unlike additional members and its expression is restricted to mast cells and basophils7. Cross-linking of CD200R3 activates these cells through an adaptor molecule DAP12 to degranulate and create cytokines such as IL-47 while CD200R transmission inhibits them21 22 In spite of rigorous investigation no apparent ligands have been recognized for CD200R-like activating receptors. The surface of mucosa and pores and skin represents a first line of defense against invading pathogens. The gastrointestinal tract is constantly and heavily loaded with nonself substances including food antigens commensal bacteria and pathogenic organisms. From the belly to the rectum the mucosa consists of a solitary coating of columnar epithelial cells organizing into crypts that invaginate into the underlying mesenchyme and villi that project into the intestinal lumen. Intestinal stem cells reside near the bottom of crypts and differentiate into unique types of epithelial cells including absorptive enterocytes and multiple secretory cells (goblet cells enteroendocrine cells and Paneth cells)23 24 Goblet cells and enteroendocrine cells secrete Rabbit Polyclonal to CLTR2. mucus and a variety of hormones respectively and happen both in villi and crypts. Paneth cells at the bottom of crypts secrete bactericidal products such as lysozyme and defensins and also provide the stem cell market. Intraepithelial lymphocytes (IELs) are a unique subset of intestinal T cells and located in the epithelial coating as solitary cells in limited association with intestinal epithelial cells with about one T cell for each and every four to nine epithelial cells in the small intestine25 26 27 In contrast to standard T cells IELs are enriched in NSC697923 T cell receptor γδ- and CD8αα-expressing cells and play important tasks through their personal connection with intestinal epithelial cells in the maintenance of mucosal homeostasis by actively or negatively regulating mucosal and acquired immunity. In the present NSC697923 study we have recognized novel CD200 homologues designated iSEC1 and iSEC2 that showed the ability of binding to CD200R but not to CD200R-like receptors. Intriguingly the manifestation of iSEC1 was limited to secretory cell lineages in gastrointestinal epithelial cells. Only IELs expressed CD200R among cells in the intestinal epithelium and NSC697923 none of intestinal epithelial cells indicated CD200 suggesting possible interaction between CD200R on IELs and iSEC1 on secretory.