Fine tuning by human CD1e of lipid-specific immune responses

Experimental Immunology, Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2011; 108(34):14228-33. DOI: 10.1073/pnas.1108809108
Source: PubMed


CD1e is a member of the CD1 family that participates in lipid antigen presentation without interacting with the T-cell receptor. It binds lipids in lysosomes and facilitates processing of complex glycolipids, thus promoting editing of lipid antigens. We find that CD1e may positively or negatively affect lipid presentation by CD1b, CD1c, and CD1d. This effect is caused by the capacity of CD1e to facilitate rapid formation of CD1-lipid complexes, as shown for CD1d, and also to accelerate their turnover. Similar results were obtained with antigen-presenting cells from CD1e transgenic mice in which lipid complexes are assembled more efficiently and show faster turnover than in WT antigen-presenting cells. These effects maximize and temporally narrow CD1-restricted responses, as shown by reactivity to Sphingomonas paucimobilis-derived lipid antigens. CD1e is therefore an important modulator of both group 1 and group 2 CD1-restricted responses influencing the lipid antigen availability as well as the generation and persistence of CD1-lipid complexes.

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    • "In the presence of CD1e, PIM6 is cleaved to PIM2 and is loaded on CD1b (25). CD1e may also positively or negatively affect lipid presentation by CD1b, CD1c, and CD1d (73). This effect is achieved by a rapid formation of CD1–lipid complexes in the presence of CD1e, and also by an accelerated turnover of formed CD1–lipid antigen complexes. "
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    ABSTRACT: T-cells recognize lipid antigens presented by dedicated antigen-presenting molecules that belong to the CD1 family. This review discusses the structural properties of CD1 molecules, the nature of mycobacterial lipid antigens, and the phenotypic and functional properties of T-cells recognizing mycobacterial lipids. In humans, the five CD1 genes encode structurally similar glycoproteins that recycle in and thus survey different cellular endosomal compartments. The structure of the CD1-lipid-binding pockets, their mode of intracellular recycling and the type of CD1-expressing antigen-presenting cells all contribute to diversify lipid immunogenicity and presentation to T-cells. Mycobacteria produce a large variety of lipids, which form stable complexes with CD1 molecules and stimulate specific T-cells. The structures of antigenic lipids may be greatly different from each other and each lipid may induce unique T-cells capable of discriminating small lipid structural changes. The important functions of some lipid antigens within mycobacterial cells prevent the generation of negative mutants capable of escaping this type of immune response. T-cells specific for lipid antigens are stimulated in tuberculosis and exert protective functions. The mechanisms of antigen recognition, the type of effector functions and the mode of lipid-specific T-cell priming are discussed, emphasizing recent evidence of the roles of lipid-specific T-cells in tuberculosis.
    Frontiers in Immunology 05/2014; 5:219. DOI:10.3389/fimmu.2014.00219
    • "The hydrophobic amino acids surrounding the pockets facilitate anchoring of the aliphatic moieties of lipid antigens, thus protecting these from aqueous surrounding. CD1e molecules never reach cell surface and are involved in processing, loading and unloading of glycolipid antigens79. Therefore, CD1e is not a bona fide antigen-presenting molecule, however, it contributes to important aspects of lipid antigen presentation. "
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    ABSTRACT: The immune system has evolved to recognize a wide range of antigenic molecules of self and non-self origin. The stimulatory antigens form complexes with antigen-presenting molecules and directly interact with the T cell receptor (TCR). Peptidic antigens associate with major histocompatibility complex (MHC) molecules and therefore, are indicated as MHC-restricted. Non-peptidic antigens do not bind to MHC molecules and are presented by other classes of antigen-presenting molecules. These non-MHC restricted antigens include glycolipid molecules, phosphorylated metabolites of the mevalonate pathway and vitamin B2 precursors. T cells specific for non-peptidic antigens have important roles in host defense against infections, autoimmunity, allergies and tumour immunosurveillance. Hence, understanding the molecular interactions between the antigen presenting cell (APC) and the T cells with non-peptidic specificity is of great relevance. Here, we review current knowledge of this type of T cells, their TCR repertoire, the structural aspects of recognized antigens, the mode of antigen recognition, and their function with special emphasis on their role in infectious diseases.
    The Indian Journal of Medical Research 11/2013; 138(5):620-31. · 1.40 Impact Factor
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    • "This results in part from its capacity to accelerate the formation and dissociation of CD1-lipid complexes. Thus, CD1e participates in antigen presentation, not only by shaping the repertoire of available lipid antigens, but also by influencing the generation and persistence of group 1 and group 2 CD1-lipid complexes; i.e., it tunes T cell responses to CD1-restricted lipid antigens in a temporal manner [4]. "
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    ABSTRACT: The CD1e protein participates in the presentation of lipid antigens in dendritic cells. Its transmembrane precursor is transported to lysosomes where it is cleaved into an active soluble form. In the presence of bafilomycin, which inhibits vacuolar ATPase and consequently the acidification of endosomal compartments, CD1e associates with a 27 kD protein. In this work, we identified this molecular partner as LAPTM5. The latter protein and CD1e colocalize in trans-Golgi and late endosomal compartments. The quantity of LAPTM5/CD1e complexes increases when the cells are treated with bafilomycin, probably due to the protection of LAPTM5 from lysosomal proteases. Moreover, we could demonstrate that LAPTM5/CD1e association occurs under physiological conditions. Although LAPTM5 was previously shown to act as a platform recruiting ubiquitin ligases and facilitating the transport of receptors to lysosomes, we found no evidence that LATPM5 controls either CD1e ubiquitination or the generation of soluble lysosomal CD1e proteins. Notwithstanding these last observations, the interaction of LAPTM5 with CD1e and their colocalization in antigen processing compartments both suggest that LAPTM5 might influence the role of CD1e in the presentation of lipid antigens.
    PLoS ONE 08/2012; 7(8):e42634. DOI:10.1371/journal.pone.0042634 · 3.23 Impact Factor
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