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CD1d function is regulated by microsomal triglyceride transfer protein

Nature Medicine volume 10, pages 535–539 (2004)Cite this article

Abstract

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-α chain (invariant NKT cells)1,2,3. The acquisition of glycolipid antigens by CD1d occurs, in part, in endosomes through the function of resident lipid transfer proteins, namely saposins4,5,6,7,8,9,10. 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 B11,12, 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.

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Figure 1: CD1d expression after Mttp deletion.
Figure 2: Deletion of Mttp inhibits CD1d-restricted presentation by hepatocytes and α-GalCer-induced hepatitis.
Figure 3: Silencing of Mttp in IECs inhibits CD1d-restricted antigen presentation.
Figure 4: Mttp deletion inhibits oxazolone-induced colitis.

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Acknowledgements

R.S.B. was supported by National Institutes of Health grants DK44319, DK53056 and DK51362; the Harvard Digestive Diseases Center; and the Broad Medical Research Program. A.K. was supported by the Max Kade Foundation. We thank D. Bailey for excellent technical assistance, A. Bendelac for DN32.D3 cells, S. Behar for CD1-restricted T-T hybridomas, H. Ploegh for MHC class I–specific antibodies, D. Meyer for endoplasmic reticulum–specific antibodies, and P. Libby, N. Davidson and A. Bendelac for critical discussions.

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Author notes

  1. Suzana Brozovic and Takashi Nagaishi: These authors contributed equally to this work.

Authors and Affiliations

  1. Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital,

    Suzana Brozovic, Takashi Nagaishi, Masaru Yoshida, Azucena Salas, Daohong Chen, Arthur Kaser, Timothy Kuo, Alicia Little, Jamin Morrison, Nadia Corazza, Jin Yong Kim & Richard S Blumberg

  2. Harvard Medical School, Boston, 02115, Massachusetts, USA

    Suzana Brozovic, Takashi Nagaishi, Masaru Yoshida, Azucena Salas, Daohong Chen, Arthur Kaser, Timothy Kuo, Alicia Little, Jamin Morrison, Nadia Corazza, Jin Yong Kim & Richard S Blumberg

  3. Program in Immunology,

    Stephanie Betz

  4. Harvard Medical School, Boston, 02115, Massachusetts, USA

    Stephanie Betz

  5. Department of Pathology, Brigham and Women's Hospital,

    Jonathan Glickman

  6. Harvard Medical School, Boston, 02115, Massachusetts, USA

    Jonathan Glickman

  7. Department of Anesthesia, Brigham and Women's Hospital,

    Sean P Colgan

  8. Harvard Medical School, Boston, 02115, Massachusetts, USA

    Sean P Colgan

  9. Gladstone Institute of Cardiovascular Disease, University of California-San Francisco, San Francisco, 94110, California, USA

    Stephen G Young

  10. Hematology-Oncology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Mark Exley

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Correspondence to Richard S Blumberg.

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Brozovic, S., Nagaishi, T., Yoshida, M. et al. CD1d function is regulated by microsomal triglyceride transfer protein. Nat Med 10, 535–539 (2004). https://doi.org/10.1038/nm1043

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