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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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).
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
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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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