Abstract
Peptide antigens are presented to T cells by major histocompatibility complex (MHC) molecules, with endogenous peptides presented by MHC class I and exogenous peptides presented by MHC class II. In contrast to the MHC system, CD1 molecules bind lipid antigens that are presented at the antigen-presenting cell (APC) surface to lipid antigen-reactive T cells1. Because CD1 molecules survey endocytic compartments2, it is self-evident that they encounter antigens from extracellular sources. However, the mechanisms of exogenous lipid antigen delivery to CD1-antigen-loading compartments are not known. Serum apolipoproteins are mediators of extracellular lipid transport for metabolic needs3. Here we define the pathways mediating markedly efficient exogenous lipid antigen delivery by apolipoproteins to achieve T-cell activation. Apolipoprotein E binds lipid antigens and delivers them by receptor-mediated uptake into endosomal compartments containing CD1 in APCs. Apolipoprotein E mediates the presentation of serum-borne lipid antigens and can be secreted by APCs as a mechanism to survey the local environment to capture antigens or to transfer microbial lipids from infected cells to bystander APCs. Thus, the immune system has co-opted a component of lipid metabolism to develop immunological responses to lipid antigens.
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References
Brigl, M. & Brenner, M. B. CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22, 817–890 (2004)
Sugita, M., Cernadas, M. & Brenner, M. B. New insights into pathways for CD1-mediated antigen presentation. Curr. Opin. Immunol. 16, 90–95 (2004)
Mahley, R. W., Weisgraber, K. H. & Farese, R. V. Jr in Williams Textbook of Endocrinology 10th edn (eds Larsen, P. R., Kronenberg, H. M., Melmed, S. & Polonsky, K. S.) 1642–1664 (Elsevier, Philadelphia, 2003)
Prigozy, T. I. et al. Glycolipid antigen processing for presentation by CD1d molecules. Science 291, 664–667 (2001)
Krul, E. S., Tikkanen, M. J., Cole, T. G., Davie, J. M. & Schonfeld, G. Roles of apolipoproteins B and E in the cellular binding of very low density lipoproteins. J. Clin. Invest. 75, 361–369 (1985)
Sacks, F. M. & Krukonis, G. P. The influence of apolipoprotein E on the interactions between normal human very low density lipoproteins and U937 human macrophages: heterogeneity among persons. Vasc. Med. 1, 9–18 (1996)
Tomiyasu, K., Walsh, B. W., Ikewaki, K., Judge, H. & Sacks, F. M. Differential metabolism of human VLDL according to content of ApoE and ApoC-III. Arterioscler. Thromb. Vasc. Biol. 21, 1494–1500 (2001)
Major, A. S. et al. Quantitative and qualitative differences in proatherogenic NKT cells in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 24, 2351–2357 (2004)
Tupin, E. et al. CD1d-dependent activation of NKT cells aggravates atherosclerosis. J. Exp. Med. 199, 417–422 (2004)
Rebbaa, A. & Portoukalian, J. Distribution of exogenously added gangliosides in serum proteins depends on the relative affinity of albumin and lipoproteins. J. Lipid Res. 36, 564–572 (1995)
Matsunaga, I. et al. Mycobacterium tuberculosis pks12 produces a novel polyketide presented by CD1c to T cells. J. Exp. Med. 200, 1559–1569 (2004)
Chaussabel, D. et al. Unique gene expression profiles of human macrophages and dendritic cells to phylogenetically distinct parasites. Blood 102, 672–681 (2003)
Le Naour, F. et al. Profiling changes in gene expression during differentiation and maturation of monocyte-derived dendritic cells using both oligonucleotide microarrays and proteomics. J. Biol. Chem. 276, 17920–17931 (2001)
Heeren, J. & Beisiegel, U. Intracellular metabolism of triglyceride-rich lipoproteins. Curr. Opin. Lipidol. 12, 255–260 (2001)
Lanzavecchia, A. Receptor-mediated antigen uptake and its effect on antigen presentation to class II-restricted T lymphocytes. Annu. Rev. Immunol. 8, 773–793 (1990)
Mahley, R. W. & Rall, S. C. Jr Apolipoprotein E: far more than a lipid transport protein. Annu. Rev. Genomics Hum. Genet. 1, 507–537 (2000)
Basu, S., Binder, R. J., Ramalingam, T. & Srivastava, P. K. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 14, 303–313 (2001)
Mahley, R. W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240, 622–630 (1988)
Beisiegel, U., Weber, W., Ihrke, G., Herz, J. & Stanley, K. K. The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein. Nature 341, 162–164 (1989)
Barak, L. S. & Webb, W. W. Fluorescent low density lipoprotein for observation of dynamics of individual receptor complexes on cultured human fibroblasts. J. Cell Biol. 90, 595–604 (1981)
Beatty, W. L. et al. Trafficking and release of mycobacterial lipids from infected macrophages. Traffic 1, 235–247 (2000)
Boullier, A. et al. Scavenger receptors, oxidized LDL, and atherosclerosis. Ann. N.Y. Acad. Sci. 947, 214–222 (2001)
Fazekas, F. et al. Apolipoprotein E epsilon 4 is associated with rapid progression of multiple sclerosis. Neurology 57, 853–857 (2001)
Shamshiev, A. et al. Self glycolipids as T-cell autoantigens. Eur. J. Immunol. 29, 1667–1675 (1999)
Brigl, M., Bry, L., Kent, S. C., Gumperz, J. E. & Brenner, M. B. Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nature Immunol. 4, 1230–1237 (2003)
Porcelli, S., Morita, C. T. & Brenner, M. B. CD1b restricts the response of human CD4-8- T lymphocytes to a microbial antigen. Nature 360, 593–597 (1992)
Moody, D. B. et al. Lipid length controls antigen entry into endosomal and nonendosomal pathways for CD1b presentation. Nature Immunol. 3, 435–442 (2002)
Innis-Whitehouse, W., Li, X., Brown, W. V. & Le, N. A. An efficient chromatographic system for lipoprotein fractionation using whole plasma. J. Lipid Res. 39, 679–690 (1998)
Brown, M. S. & Goldstein, J. L. A receptor mediated pathway fpr cholesterol homeostasis. Science 232, 34–47 (1986)
Acknowledgements
We thank B. Asfaw, J. Heeren and S. Blacklow for helpful discussion, and D. Chausabel for providing additional microarray data. P.vdE., S.G., L.L., M. Brigl, E.L., J.G., C.C.D. and M. Brenner are funded by the NIH. L.L. is the recipient of a Howard Hughes Gilliam fellowship. Funding for T.-Y.C. and D.B.M. was from the Pew Foundation Scholars in the Biomedical Sciences, the Cancer Research Institute and the NIH. Funding for G.S.B., a Lister-Jenner Research Fellow, and for P.A.I. was from the Medical Research Council and the Wellcome Trust. S.C.K. was funded by the Boston Area Diabetes Research Center (BADERC).
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This file contains the following: additional calculations, Supplementary Figure Legends, Supplementary Figures S1-S4 and additional references. (PDF 50 kb)
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Elzen, P., Garg, S., León, L. et al. Apolipoprotein-mediated pathways of lipid antigen presentation. Nature 437, 906–910 (2005). https://doi.org/10.1038/nature04001
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DOI: https://doi.org/10.1038/nature04001
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