Abstract
CD200R is an inhibitory receptor expressed on myeloid cells and some lymphoid cells, and plays important roles in negatively regulating immune responses. CD200 is the only known ligand of CD200R and broadly distributed in a variety of cell types. Here we identified novel CD200 homologues, designated iSEC1 and iSEC2, that are expressed exclusively by secretory cell lineages in the gastrointestinal epithelium while authentic CD200 is expressed by none of epithelial cells including secretory cells. Both iSEC1 and iSEC2 could bind to CD200R but not other members of the CD200R family. Notably, CD200R expression was confined to intraepithelial lymphocytes (IELs) among cells in the gastrointestinal epithelium. Binding of iSEC1 to CD200R on IELs resulted in the suppression of cytokine production 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.
Highlights
The surface of mucosa and skin represents a first line of defense against invading pathogens
We have identified two membrane-bound proteins in mice, iSEC1 and iSEC2, as novel CD200R ligands that are expressed exclusively in secretory cell lineages of the intestinal epithelium, including goblet cells, enteroendocrine cells, and Paneth cells, in contrast to much broader expression of CD200
We demonstrated in the present study that binding of iSEC1 to CD200R on Intraepithelial lymphocytes (IELs) attenuates cytokine production and cytolytic activity by activated IELs in vitro
Summary
The surface of mucosa and skin represents a first line of defense against invading pathogens. From the stomach to the rectum, the mucosa consists of a single layer 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 distinct types of epithelial cells, including absorptive enterocytes and multiple secretory cells (goblet cells, enteroendocrine cells, and Paneth cells)[23,24]. In contrast to conventional T cells, IELs are enriched in T cell receptor γδ- and CD8αα-expressing cells, and play important roles through their intimate interaction with intestinal epithelial cells in the maintenance of mucosal homeostasis by actively or negatively regulating mucosal and acquired immunity. IELs expressed CD200R among cells in the intestinal epithelium, and none of intestinal epithelial cells expressed CD200, suggesting possible interaction between CD200R on IELs and iSEC1 on secretory cells in the intestinal epithelium. Binding of iSEC1 to CD200R on IELs attenuated the cytokine production and cytolytic activity of activated IELs, demonstrating that iSEC1 is a functional ligand of CD200R, and may negatively regulate the function of IELs
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