1. Department of Pathology,
2. Department of Medicine, Division of Rheumatology, Immunology and Allergy, and
3. Center for Neurologic Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
4. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA
5. School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

Correspondence to: Michael B. Brenner² Correspondence and requests for materials should be addressed to M.B. (Email: mbrenner@rics.bwh.harvard.edu).

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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