Presentation of the Same Glycolipid by Different CD1 Molecules

Shamshiev, Abdijapar; Gober, Hans Jürgen; Donda, Alena; Mazorra, Zaima; Mori, Lucia; Libero, Gennaro De

doi:10.1084/jem.20011963

Cited by 196 publications

(206 citation statements)

References 40 publications

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“…We previously reported that both wild-type and soluble mCD1d1 assemble with PI and PI-glycans in vivo (11,12). However, in vitro, CD1 appears to bind a wide variety of lipids that vary in the chemical character of the moiety that directly interacts with the antigen-binding groove (11,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Therefore, our previous findings (11,12) may have been biased by the techniques used for the extraction, purification, and analyses of mCD1d1-associated ligands.…”

Section: Resultsmentioning

confidence: 79%

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Lipid–protein interactions: Biosynthetic assembly of CD1 with lipids in the endoplasmic reticulum is evolutionarily conserved

Park

Kang

Silva

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The CD1 family consists of lipid antigen-presenting molecules, which include group I CD1a, CD1b, and CD1c and group II CD1d proteins. Topologically, they resemble the classical peptide antigen-presenting MHC molecules except that the large, exclusively nonpolar and hydrophobic, antigen-binding groove of CD1 has evolved to present cellular and pathogen-derived lipid antigens to specific T lymphocytes. As an approach to understanding the biochemical basis of lipid antigen presentation by CD1 molecules, we have characterized the natural ligands associated with mouse CD1d1 as well as human CD1b and CD1d molecules. We found that both group I and II CD1 molecules assemble with cellular phosphatidylinositol (PI), which contains heterogeneous fatty acyl chains. Further, this assembly occurs within the endoplasmic reticulum. Because the structures of the antigen-binding grooves of CD1a and CD1c closely resemble those of CD1b and CD1d, we conclude that the assembly of CD1 molecules with PI in the endoplasmic reticulum is evolutionarily conserved. These findings suggest that PI plays a chaperone-like role in CD1 assembly, possibly to preserve the integrity of the antigen-binding groove until CD1 binds antigenic lipids in the endocytic pathway.

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Section: Resultsmentioning

confidence: 79%

“…These lipids include cellular phospholipids and sphingolipids as well as mycobacterial phospholipids and mycolates (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Remarkably, however, CD1 molecules appear to associate with a restricted variety of lipids in vivo.…”

Section: Discussionmentioning

confidence: 99%

Lipid–protein interactions: Biosynthetic assembly of CD1 with lipids in the endoplasmic reticulum is evolutionarily conserved

Park

Kang

Silva

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…CD1 proteins present a variety of pathogen-derived lipids to T cells in vitro (1)(2)(3)(4)(5)(6), and T cells reactive to mycobacterial lipid Ags have been isolated from the bloodstream of tuberculosis patients, providing evidence that CD1 and lipid-reactive T cells normally function in the host response during infections with Mycobacterium tuberculosis (7)(8)(9). However, CD1-mediated T cell responses are not limited only to foreign pathogens, as endogenous mammalian phosphatidylinositols normally bind to cellular CD1 proteins as they traverse the secretory pathway (10,11), and self gangliosides, phosphatidylinositols, sulfatides, and isoglobosides activate CD1-restricted T cells (12)(13)(14)(15)(16). Thus, mammalian APCs normally encounter and present both foreign and self lipid Ags to T cells, raising basic questions about how such responses are regulated.…”

mentioning

confidence: 99%

Mycobacterium tuberculosisRegulates CD1 Antigen Presentation Pathways through TLR-2

Roura-Mir

Wang

Cheng

et al. 2005

The Journal of Immunology

115

113

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Mycobacterium tuberculosis remains a major pathogen of worldwide importance, which releases lipid Ags that are presented to human T cells during the course of tuberculosis infections. Here we report that cellular infection with live M. tuberculosis or exposure to mycobacterial cell wall products converted CD1− myeloid precursors into competent APCs that expressed group 1 CD1 proteins (CD1a, CD1b, and CD1c). The appearance of group 1 CD1 proteins at the surface of infected or activated cells occurred via transcriptional regulation, and new CD1 protein synthesis and was accompanied by down-regulation of CD1d transcripts and protein. Isolation of CD1-inducing factors from M. tuberculosis using normal phase chromatography, as well as the use of purified natural and synthetic compounds, showed that this process involved polar lipids that signaled through TLR-2, and we found that TLR-2 was necessary for the up-regulation of CD1 protein expression. Thus, mycobacterial cell wall lipids provide two distinct signals for the activation of lipid-reactive T cells: lipid Ags that activate T cell receptors and lipid adjuvants that activate APCs through TLR-2. These dual activation signals may represent a system for selectively promoting the presentation of exogenous foreign lipids by those myeloid APCs, which come into direct contact with pathogens.

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“…This might reflect intrinsic structural features limiting their antigenicity and/or a difficulty in breaking tolerance to self. Some GSL, such as sulphatide, form stimulatory complexes with all CD1 molecules, thus behaving as promiscuous antigens [1].…”

Section: Structure Of Exogenous and Self-lipid Antigensmentioning

confidence: 99%

“…An intriguing issue is how the route of internalization contributes to lipid antigenicity. Sulphatide, which is internalized by clathrin-coated vesicles, can form complexes with all CD1 molecules [1], suggesting that this type of internalization is permissive for the generation of all types of CD1 complexes. Whether glycolipids that are internalized through caveolae can also form complexes with all CD1 molecules remains unknown.…”

Section: Lipid Traffic Within Cellsmentioning

confidence: 99%

The cellular and biochemical rules of lipid antigen presentation

2009

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The recognition of both protein and lipid antigens follows similar strategies that rely on different molecular mechanisms. APC present lipid antigens exploiting the same mechanisms implicated in lipid translocation, lipoprotein assembly and lipid degradation. An important issue is how the lipid structure contributes to antigenicity. Lipid hydrophobicity influences the modes of internalization by APC, the trafficking through different membrane compartments, the binding to CD1 molecules and the stability of antigenic complexes. Some glycolipids with large hydrophilic parts require processing of the sugar moieties exerted by lysosomal hydrolases. Finally, extraction of lipids from membranes, their solubilization and loading on CD1 molecules are facilitated by the same lysosomal lipid-binding proteins that are also instrumental in lipid catabolism. More recent investigations reveal how lipid-specific immunity is regulated during infections. In this review we describe the main cellular and biochemical rules of lipid antigen presentation and discuss their implications in anti-microbial and autoimmune responses.Key words: Antigen recognition . CD1 . Lipid antigens . TCR IntroductionMembers of the MHC or CD1 families present protein and lipid antigens to T cells, respectively. CD1 molecules are differentially expressed by a variety of cell types including DC, B cells, monocytes, Langerhans cells, stellate hepatic cells, epithelial cells, microglial cells and keratinocytes. In humans, five genes (CD1A, B, C, D and E) encode CD1 proteins. CD1a, CD1b, CD1c and CD1d molecules reach the plasma membrane and are involved in lipid presentation to T cells, whereas CD1e remains intracellular and is involved in lipid processing. Lipid-specific T cells express a variety of TCR heterodimers, with the exception of invariant NKT (iNKT) cells, a CD1d-restricted population that uses a semi-invariant TCR (invariant Va24-Ja18 and variable Vb11 chains in humans, invariant Va14-Ja18 and variable Vb8.2, Vb7 or Vb2 chains in mice).Proteins become antigenic after a series of events starting with partial degradation by the cellular machinery represented by the proteasome or by proteases located in lysosomes (Ly) and endoplasmic reticulum (ER). This immunological function, commonly known as antigen processing, leads to the generation of peptide fragments that are carried to the proximity of MHC molecules with which they form antigenic complexes. A similar scheme applies to the presentation of lipid antigens. Lipids derived from extracellular routes are internalized or alternatively, self-lipid antigens are synthesized within the APC. These lipids are then transported into the cellular compartments where CD1 molecules traffic and after loading onto CD1, form antigenic complexes.The physicochemical properties of lipids and peptides impose the utilization of different strategies by the APC to digest, transport and load each of these classes of molecules. Antigenicity of lipids is achieved with the participation of extracellular and intracellular li...

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Presentation of the Same Glycolipid by Different CD1 Molecules

Cited by 196 publications

References 40 publications

Lipid–protein interactions: Biosynthetic assembly of CD1 with lipids in the endoplasmic reticulum is evolutionarily conserved

Lipid–protein interactions: Biosynthetic assembly of CD1 with lipids in the endoplasmic reticulum is evolutionarily conserved

Mycobacterium tuberculosisRegulates CD1 Antigen Presentation Pathways through TLR-2

The cellular and biochemical rules of lipid antigen presentation

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