title: Ligation of intestinal epithelial CD1d induces bioactive IL-10: critical role of the cytoplasmic tail in autocrine signaling.
abstract: The intestinal epithelium is anatomically positioned to serve as the critical interface between the lumen and the mucosal immune system. In addition to MHC class I and II antigens, intestinal epithelia constitutively express the nonclassical MHC molecule CD1d, a transmembrane molecule with a short cytoplasmic tail expressed as a beta(2)-microglobulin-associated 48-kDa glycoprotein and novel beta(2)-microglobulin-independent 37-kDa nonglycosylated protein on intestinal epithelia. At present, it is not known whether extracellular ligands can signal intestinal epithelial CD1d. To define signaling of CD1d cytoplasmic tail, retrovirus-mediated gene transfer was used to generate stable cell lines expressing wild-type CD1d or a chimeric molecule (extracellular CD1d and cytoplasmic CD1a), and surface CD1d was triggered by antibody crosslinking. Although wild-type CD1d was readily activated (tyrosine phosphorylation), no demonstrable signal was evident in cell lines expressing the chimeric molecule. Subsequent studies revealed that anti-CD1d crosslinking specifically induces epithelial IL-10 mRNA and protein and is blocked by the tyrosine kinase inhibitor genistein. Further studies addressing epithelial-derived IL-10 revealed that anti-CD1d crosslinking attenuates IFN-gamma signaling and that such attenuation is reversed by addition of functionally inhibitory IL-10 antibodies. These results define signaling through surface CD1d, and, importantly, they demonstrate that this pathway may serve to dampen epithelial proinflammatory signals.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. colgan@zeus.bwh.harvard.edu
authors.forename: S P
authors.initials: SP
authors.lastname: Colgan
authors.forename: R M
authors.initials: RM
authors.lastname: Hershberg
authors.forename: G T
authors.initials: GT
authors.lastname: Furuta
authors.forename: R S
authors.initials: RS
authors.lastname: Blumberg
mesh_terms: D018949:Antigens, CD1 / Q000235:genetics / Q000276:immunology*; D055610:Antigens, CD1d; D019898:Autocrine Communication; D018938:Caco-2 Cells; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D003593:Cytoplasm / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D019073:HT29 Cells; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology*; D010766:Phosphorylation; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; C526877:CD1D protein, human; D003432:Cross-Linking Reagents; D016753:Interleukin-10; D014443:Tyrosine