Letter | Published:

CD1d function is regulated by microsomal triglyceride transfer protein

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. 1

    Lantz, O. & Bendelac, A. An invariant T cell receptor α chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD8+ T cells in mice and humans. J. Exp. Med. 180, 1097–1106 (1994).

  2. 2

    Behar, S.M., Podrebarac, T.A., Roy, C.J., Wang, C.R. & Brenner, M.B. Diverse TCRs recognize murine CD1. J. Immunol. 162, 161–167 (1999).

  3. 3

    Kronenberg, M. & Gapin, L. The unconventional lifestyle of NKT cells. Nat. Rev. Immunol. 2, 557–568 (2002).

  4. 4

    De Silva, A.D. et al. Lipid protein interactions: the assembly of CD1d1 with cellular phospholipids occurs in the endoplasmic reticulum. J. Immunol. 168, 723–733 (2002).

  5. 5

    Kang, S.J. & Cresswell, P. Calnexin, calreticulin, and Erp57 cooperate in disulfide bond formation in human CD1d heavy chain. J. Biol. Chem. 277, 44838–44844 (2002).

  6. 6

    Prigozy, T.I. et al. Glycolipid antigen processing for presentation by CD1d molecules. Science 291, 664–667 (2001).

  7. 7

    Roberts, T.J. et al. Recycling CD1d1 molecules present endogenous antigens processed in an endocytic compartment to NKT cells. J. Immunol. 168, 5409–5414 (2002).

  8. 8

    Zhu, D. et al. Editing of CD1d-bound lipid antigens by endosomal lipid transfer proteins. Science 303, 523–527 (2004).

  9. 9

    Kant, S.J. & Cresswell, P. Saposins facilitate CD1d-restricted presentation of an exogenous lipid antigen to T cells. Nat. Immunol. 5, 175–181 (2004).

  10. 10

    Winau, F. et al. Saposin C is required for lipid presentation by human CD1b. Nat. Immunol. 5, 169–174 (2004).

  11. 11

    Gordon, D.A., Wetterau, J.R. & Gregg, R.E. Microsomal triglyceride transfer protein: a protein complex required for the assembly of lipoprotein particles. Trends Cell. Biol. 5, 317–321 (1995).

  12. 12

    Wetterau, J.R., Combs, K.A., Spinner, S.N. & Joiner, B.J. Protein disulfide isomerase is a component of the microsomal triglyceride transfer protein complex. J. Biol. Chem. 265, 9800–9807 (1990).

  13. 13

    Cui, J. et al. Requirement for Vα14 NKT cells in IL-12-mediated rejection of tumors. Science 278, 1623–1626 (1997).

  14. 14

    Nieuwenhuis, E.E. et al. CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung. Nat. Med. 8, 588–593 (2002).

  15. 15

    Vincent, M.S., Gumperz, J.E. & Gumperz, M.B. Understanding the function of CD1-restricted T cells. Nat. Immunol. 4, 517–523 (2003).

  16. 16

    Gumperz, J.E. et al. Murine Cd1d-restricted T cell recognition of cellular lipids. Immunity 12, 211–221 (2000).

  17. 17

    Joyce, S. et al. Natural ligand of mouse CD1d1: cellular glycosylphospha-tidylinositol. Science 279, 1541–1544 (1998).

  18. 18

    Park, J.J. et al. Lipid-protein interactions: biosynthetic assembly of CD1 with lipids in the endoplasmic reticulum is evolutionarily conserved. Proc. Natl. Acad. Sci. USA 101, 1022–1026 (2004).

  19. 19

    Atzel, A. & Wetterau, J.R. Mechanism of microsomal triglyceride transfer protein catalyzed lipid transport. Biochemistry 32, 10444–10450 (1993).

  20. 20

    Jamil, H. et al. Microsomal triglyceride transfer protein – specificity of lipid binding and transport. J. Biol. Chem. 270, 6549–6554 (1995).

  21. 21

    Raabe, M. et al. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice. J. Clin. Invest. 103, 1287–1298 (1999).

  22. 22

    Bleicher, P.A. et al. Expression of murine CD1 on gastrointestinal epithelium. Science 250, 679–682 (1990).

  23. 23

    Bjorkegren, J., Beigneux, A., Bergo, M.O., Maher, J.J. & Young, S.G. Blocking the secretion of hepatic very low density lipoproteins renders the liver more susceptible to toxin-induced injury. J. Biol. Chem. 277, 5476–5483 (2002).

  24. 24

    Ralf, K., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427–1429 (1995).

  25. 25

    Osman, Y. et al. Activation of hepatic NKT cells and subsequent liver injury following administration of α-galactosylceramide. Eur. J. Immunol. 30, 1919–1928 (2000).

  26. 26

    van de Wal, Y. et al. Delineation of a CD1d-restricted antigen presentation pathway associated with human and mouse intestinal epithelial cells. Gastroenterology 124, 1420–1431 (2003).

  27. 27

    Heller, F., Fuss, I.J., Nieuwenhuis, E., Blumberg, R.S. & Strober, W. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-cells. Immunity 17, 629–638 (2002).

  28. 28

    Davidson, N.O. & Shelness, G.S. Apolipoprotein B: mRNA editing, lipoprotein assembly, and presecretory degradation. Annu. Rev. Nutr. 20, 169–193 (2000).

  29. 29

    Bendelac, A. et al. CD1 recognition by mouse NK1+ T lymphocytes. Science 268, 863–865 (1995).

  30. 30

    Chen, D. et al. Carcinoembryonic antigen-related cellular adhesion molecule 1 isoforms alternatively inhibit and costimulate human T cell function. J. Immunol. 172, 3535–3543 (2004).

Download references

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.

Author information

Competing interests

The authors declare no competing financial interests.

Correspondence to Richard S Blumberg.

Supplementary information

  1. Supplementary Fig. 1 (PDF 991 kb)

  2. Supplementary Table 1 (PDF 9 kb)

Rights and permissions

Reprints and Permissions

About this article

Further reading

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.