Research Focus Serum lipoproteins: Trojan horses of the immune response? Jens Schu ¨ mann and Gennaro De Libero Experimental Immunology, Department of Research, University Hospital, Basel, Switzerland T cells recognizing lipid antigens presented by CD1 molecules have an important role in the immune response. Several lipid antigens for CD1-restricted T cells have been identified, as have some rules of CD1 loading and CD1-restricted presentation. Little is known, however, about the delivery of lipid antigens from either extracellu- lar compartments or CD1-negative cells to CD1-expres- sing antigen-presenting cells (APCs). A recent study provides evidence for a role for apolipoprotein E in binding lipid antigens and delivering them to APCs. Introduction There is increasing evidence that T cells that recognize lipid antigens loaded on CD1 presenting molecules (CD1a–d in humans and CD1d in mice) contribute to immunological defence against infections, tumours, and autoimmune diseases and probably also promote chronic inflammation in atherosclerosis [1]. Loading of CD1 molecules with immunologically relevant lipid antigens occurs within endosomal compartments [2] or directly on the cell surface [3]. Lipid antigens are water insoluble, a physical property that implies transport mechanisms distinct from those of protein antigens. Lipid solubility is facilitated by lipid transfer proteins that bind lipids and render them available to cells. Indeed, in late endosomes and lysosomes, loading of CD1 with lipid antigens is facilitated by lipid transfer proteins (e.g. saposins) [4], which also participate in the degradation of glycosphingo- lipids. Another example of an immunologically relevant lipid-solubilizing protein is CD1e, a member of CD1 family that has evolved as a soluble lipid-binding protein assisting the processing of complex microbial antigens [5]. Apolipoproteins as carriers of lipid antigens to antigen-presenting cells Not all cells express CD1 molecules, but they can be infected, transformed or metabolically altered and be a source of lipid antigen(s). Furthermore, infectious agents in the extracellular compartment probably release lipid antigen(s) within the extracellular milieu. An important issue therefore concerns how, in the context of infections, tumours, autoimmune diseases and atherosclerosis, lipid antigens encounter the endosomal compartments of CD1 C antigen-presenting cells (APCs). This issue was first addressed by Schaible et al. [6], who showed that apoptotic bodies from mycobacteria-infected cells are an efficient vehicle for lipid transport to the endosomal compartments of neighbouring APCs. A second mechanism dependent upon lipoproteins has now been demonstrated by van den Elzen et al. [7]. They convincingly show that galactosyl( a1/2)galactosyl ceramide (GGC), an artificial lipid antigen requiring lysosomal trafficking and processing [8], can bind to the apolipoprotein E (ApoE) component of very low density lipoproteins (VLDLs) in human serum or to ApoE, which is secreted from macrophages or dendritic cells. ApoE then strongly accelerates the transport of GGC into the endosomal compartments relevant for lipid antigen processing and CD1 loading inside APC. Cellular uptake of ApoE-bound GGC by APCs depends partly on the LDL receptor and also on other lipoprotein receptors whose expression and role in the immune system have not yet been well studied. Receptor-mediated endocytosis of ApoE represents a system that efficiently and specifically internalizes ApoE-associated lipid antigens into cells expressing the relevant lipoprotein receptors. ApoE also enhances transfer of mycobacterial lipids to CD1-expressing APCs. Using CD1-negative macrophages infected with Mycobacterium tuberculosis, van den Elzen et al. [7] could track the transfer of mycobacterial lipids via ApoE to the endosomal compartment of adjacent cells. This transfer mechanism might be relevant for cross- presentation of mycobacterial lipid antigens. Although the experiment that completes the picture and demonstrates that non-infected APCs become stimulatory still needs to be done, this scenario appears the most likely. If ApoE is important in the transfer of exogenous lipids, is it also relevant for the transport of self lipid antigens? ApoE K/K mice are not deficient in CD1-restricted T cells, thus excluding a relevant mechanism for ApoE-mediated transport of endogenous lipid antigens to cells mediating selection of this T cell population. ApoE could, however, be relevant for lipid antigen delivery in the periphery during the entire life span, supported by the finding that there are fewer CD1d-restricted NK T cells in aged ApoE- deficient mice [9]. ApoE might also be important in the transfer of self lipid antigens that are targets of autoimmune attack. ApoE associates with sulfatide, a myelin-derived glyco- lipid, in cerebrospinal fluid and regulates the brain sulfatide levels [10]. Moreover, ApoE-deficient mice show exacerbated experimental allergic encephalomyelitis (EAE) [11]. This might be a consequence of reduced priming of sulfatide-specific CD1d-restricted regulatory Corresponding author: De Libero, G. (gennaro.delibero@unibas.ch). Available online 27 December 2005 Update TRENDS in Immunology Vol.27 No.2 February 2006 www.sciencedirect.com