CD1d function is regulated by microsomal triglyceride transfer protein.
CD1d is a major histocompatibility complex (MHC) class I-related molecule that functions in glycolipid antigen presentation to distinct subsets of T cells that express natural killer receptors and an invariant T-cell receptor-alpha chain (invariant NKT cells). The acquisition of glycolipid antigens by CD1d occurs, in part, in endosomes through the function of resident lipid transfer proteins, namely saposins. Here we show that microsomal triglyceride transfer protein (MTP), a protein that resides in the endoplasmic reticulum of hepatocytes and intestinal epithelial cells (IECs) and is essential for lipidation of apolipoprotein B, associates with CD1d in hepatocytes. Hepatocytes from animals in which Mttp (the gene encoding MTP) has been conditionally deleted, and IECs in which Mttp gene products have been silenced, are unable to activate invariant NKT cells. Conditional deletion of the Mttp gene in hepatocytes is associated with a redistribution of CD1d expression, and Mttp-deleted mice are resistant to immunopathologies associated with invariant NKT cell-mediated hepatitis and colitis. These studies indicate that the CD1d-regulating function of MTP in the endoplasmic reticulum is complementary to that of the saposins in endosomes in vivo.
Brozovic
Suzana
S
Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nagaishi
Takashi
T
Yoshida
Masaru
M
Betz
Stephanie
S
Salas
Azucena
A
Chen
Daohong
D
Kaser
Arthur
A
Glickman
Jonathan
J
Kuo
Timothy
T
Little
Alicia
A
Morrison
Jamin
J
Corazza
Nadia
N
Kim
Jin Yong
JY
Colgan
Sean P
SP
Young
Stephen G
SG
Exley
Mark
M
Blumberg
Richard S
RS
D000012:Abetalipoproteinemia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D018949:Antigens, CD1 / Q000502:physiology*; D055610:Antigens, CD1d; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D018076:DNA, Complementary / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000502:physiology; D020868:Gene Silencing; D022781:Hepatocytes / Q000276:immunology / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology; D008099:Liver / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016176:T-Lymphocyte Subsets / Q000276:immunology
D018949:Antigens, CD1; D055610:Antigens, CD1d; D002352:Carrier Proteins; D018076:DNA, Complementary; C106092:microsomal triglyceride transfer protein