Self glycolipids as T-cell autoantigens

Shamshiev, Abdijapar; Donda, Alena; Carena, Ilaria; Mori, Lucia; Kappos, Ludwig; Libero, Gennaro De

doi:10.1002/(sici)1521-4141(199905)29:05<1667::aid-immu1667>3.0.co;2-u

Cited by 253 publications

(196 citation statements)

References 30 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: 96%

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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: 96%

“…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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“…The finding that DN T cells from SLE patients are restricted by CD1c raises the possibility that a nonpeptide self-Ag is presented to T cells. We hypothesize that cardiolipin and other self-glycolipids are ligands for CD1c-directly reactive T cells given the prominence of anticardiolipin Abs in SLE, the presence of CL in plasma lipoproteins (39), their structural similarity (polar head group with lipid tail) with other CD1-restricted T cell ligands (9,(11)(12)(13)(14)(15)37), and the recent report of T cell recognition of self-glycolipids (40).…”

Section: Discussionmentioning

confidence: 99%

Human Double-Negative T Cells in Systemic Lupus Erythematosus Provide Help for IgG and Are Restricted by CD1c

Sieling¹,

Porcelli

Duong³

et al. 2000

The Journal of Immunology

115

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To understand the mechanism of T cell help for IgG production in systemic lupus erythematosus (SLE) we investigated the response of CD4- and CD8-negative (double-negative (DN)) T cells because 1) DN T cells are present at unusually high frequency in patients with SLE and can induce pathogenic autoantibodies; 2) the DN T cell repertoire includes cells restricted by CD1 Ag-presenting molecules; and 3) CD1c is expressed on a population of circulating B cells. We derived DN T cell lines from SLE patients and healthy individuals. In the presence of CD1+ APCs, DN T cell lines from SLE patients produced both IL-4 and IFN-γ, whereas DN T cells from healthy donors produced IFN-γ, but no IL-4. In general, cells from patients with highly active disease produced high levels of IFN-γ; cells from those with little activity produced high IL-4. Coculture of CD1c-directly reactive T cells from healthy donors with CD1c+ B cells elicited IgM Abs, but little or no IgG. In contrast, CD1c-directly reactive T cells from SLE patients induced isotype switching, with a striking increase in IgG production. Neutralizing Abs to CD1c inhibited the ability of DN T cells to induce IgG production from CD1c+ B cells, further indicating that CD1c mediated the T and B cell interaction. IgG production was also inhibited by neutralizing Abs to IL-4, correlating with the cytokine pattern of DN T cells derived from these patients. The data suggest that CD1c-restricted T cells from SLE patients can provide help to CD1c+ B cells for IgG production and could therefore promote pathogenic autoantibody responses in SLE.

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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

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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Self glycolipids as T-cell autoantigens

Cited by 253 publications

References 30 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

Human Double-Negative T Cells in Systemic Lupus Erythematosus Provide Help for IgG and Are Restricted by CD1c

Mycobacterium tuberculosisRegulates CD1 Antigen Presentation Pathways through TLR-2

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