The Journal of Experimental Medicine
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Published online February 20, 2007
doi:10.1084/jem.20062006
The Journal of Experimental Medicine, Vol. 204, No. 3, 533-545
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Dougan et al.
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ARTICLE

 MTP regulated by an alternate promoter is essential for NKT cell development

Stephanie K. Dougan1,2, Paul Rava3, M. Mahmood Hussain3, and Richard S. Blumberg1

1 Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115
2 Program in Immunology, Harvard Medical School, Boston, MA 02115
3 Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY 11203

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

Microsomal triglyceride transfer protein (MTP), an endoplasmic reticulum lipid transfer protein critical for apolipoprotein B (apoB) secretion, regulates CD1d antigen presentation. We identified MTP variant 1 (MTPv1), a novel splice variant of mouse MTP, by polymerase chain reaction and Northern analysis in non–apoB-secreting tissues, including thymocytes and antigen-presenting cells (APCs). Edman degradation of MTPv1 isolated from transfected cells revealed three unique residues; however, recombinant MTP and MTPv1 had an equivalent protein disulfide isomerase association, subcellular localization, triglyceride transfer, phospholipid transfer, response to inhibitors, and ability to support apoB secretion. MTP and MTPv1 efficiently transferred phosphatidylethanolamine to CD1d in vitro. NKT cells fail to develop in fetal thymic organ culture (FTOC) treated with MTP antagonists. MTP-inhibited FTOCs produced negligible numbers of CD1d tetramer–positive cells and exhibited marked defects in IL-4 production upon stimulation with anti-CD3 or {alpha}-galactosylceramide–pulsed APCs. CD1d expression on CD4+CD8+ FTOC cells was unaffected by MTP inhibition. Thus, our results demonstrate that MTPv1 in thymocytes is critical to NKT cell development. We hypothesize that, when MTP is inactive, CD1d traffics to the cell surface and presents no lipid or a lipid that is incapable of mediating NKT cell selection and/or is refractory to lysosomal editing.

Abbreviations used: 9-FL, 9-fluoronyl carboxylic acid; {alpha}-galcer, {alpha}-galactosylceramide; apoB, apolipoprotein B; FTOC, fetal thymic organ culture; IEC, intestinal epithelial cell; ION, ionomycin; MFI, median fluorescence intensity; MTP, microsomal triglyceride transfer protein; MTPv1, MTP variant 1; NBD, 7-nitro-2,1,3-benzoxadiazol-4-yl; PDI, protein disulfide isomerase; PE, phosphatidylethanolamine; RACE, rapid amplification of cDNA ends; VLDL, very low density lipoprotein.


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