The Journal of Experimental Medicine
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Published online 8 August 2005 doi:10.1084/jem.20050183
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 4, 529-539
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ARTICLE

 Microsomal triglyceride transfer protein lipidation and control of CD1d on antigen-presenting cells

Stephanie K. Dougan1,2, Azucena Salas1, Paul Rava4, Amma Agyemang2,3, Arthur Kaser1, Jamin Morrison1, Archana Khurana5, Mitchell Kronenberg5, Caroline Johnson4, Mark Exley3, M. Mahmood Hussain4, and Richard S. Blumberg1

1 Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
2 Program in Immunology, Division of Medical Sciences
3 Division of Hematology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
4 Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY 11203
5 Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121

CORRESPONDENCE Richard S. Blumberg: rblumberg{at}partners.org

Microsomal triglyceride transfer protein (MTP), an endoplasmic reticulum (ER) chaperone that loads lipids onto apolipoprotein B, also regulates CD1d presentation of glycolipid antigens in the liver and intestine. We show MTP RNA and protein in antigen-presenting cells (APCs) by reverse transcription–polymerase chain reaction and by immunoblotting of mouse liver mononuclear cells and mouse and human B cell lines. Functional MTP, demonstrated by specific triglyceride transfer activity, is present in both mouse splenocytes and a CD1d-positive mouse NKT hybridoma. In a novel in vitro transfer assay, purified MTP directly transfers phospholipids, but not triglycerides, to recombinant CD1d. Chemical inhibition of MTP lipid transfer does not affect major histocompatibility complex class II presentation of ovalbumin, but considerably reduces CD1d-mediated presentation of {alpha}-galactosylceramide ({alpha}-galcer) and endogenous antigens in mouse splenic and bone marrow–derived dendritic cells (DCs), as well as in human APC lines and monocyte-derived DCs. Silencing MTP expression in the human monocyte line U937 affects CD1d function, as shown by diminished presentation of {alpha}-galcer. We propose that MTP acts upstream of the saposins and functions as an ER chaperone by loading endogenous lipids onto nascent CD1d. Furthermore, our studies suggest that a small molecule inhibitor could be used to modulate the activity of NKT cells.

Abbreviations used: {alpha}-galcer, {alpha}-galactosylceramide; apoB, apolipoprotein B; ß2m, ß2- microglobulin; BMDC, BM- derived DC; ER, endoplasmic reticulum; IEC, intestinal epithelial cell; LMNC, liver mononuclear cell; MFI, mean fluorescence intensity; moDC, monocyte- derived DC; MTP, microsomal triglyceride transfer protein; NBD, 7-nitro-2,1,3-benzoxadiazol-4-yl; PDI, protein disulfide isomerase; PE, phosphatidyl ethanolamine; pIpC, poly-inositic:poly-cytodylic acid; si, small interfering.


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