Ligation of intestinal epithelial CD1d induces bioactive IL-10: critical role of the cytoplasmic tail in autocrine signaling.
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.
Colgan
S P
SP
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
Hershberg
R M
RM
Furuta
G T
GT
Blumberg
R S
RS
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
D018949:Antigens, CD1; D055610:Antigens, CD1d; C526877:CD1D protein, human; D003432:Cross-Linking Reagents; D016753:Interleukin-10; D014443:Tyrosine