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

Sieling, Peter A.; Porcelli, Steven A.; Duong, Baochau T.; Spada, Fabio; Bloom, Barry R.; Diamond, Betty; Hahn, Bevra H.

doi:10.4049/jimmunol.165.9.5338

Cited by 115 publications

(86 citation statements)

References 55 publications

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“…Such findings are in keeping with previous reports (56,57) and, more generally, with helper activity by CD1-restricted T cells (58). The contribution of PL-specific T cells to allergic reactions in the lung of pollen-sensitive patients is not demonstrable with in vitro experiments, and therefore we can only speculate about their role in the pathogenesis of this disease.…”

Section: Articlesupporting

confidence: 92%

Human CD1-restricted T-cell recognition of lipids from pollens

Spinozzi¹,

Agea²,

Corazzi³

et al. 2002

Journal of Allergy and Clinical Immunology

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Plant pollens are an important source of environmental antigens that stimulate allergic responses. In addition to acting as vehicles for foreign protein antigens, they contain lipids that incorporate saturated and unsaturated fatty acids, which are necessary in the reproduction of higher plants. The CD1 family of nonpolymorphic major histocompatibility complex-related molecules is highly conserved in mammals, and has been shown to present microbial and self lipids to T cells. Here, we provide evidence that pollen lipids may be recognized as antigens by human T cells through a CD1-dependent pathway. Among phospholipids extracted from cypress grains, phosphatidyl-choline and phosphatidylethanolamine were able to stimulate the proliferation of T cells from cypress-sensitive subjects. Recognition of phospholipids involved multiple cell types, mostly CD4 ϩ T cell receptor for antigen (TCR) ␣␤ ϩ , some CD4 Ϫ CD8 Ϫ TCR ␥␦ ϩ , but rarely V ␣ 24 i ϩ natural killer-T cells, and required CD1a ϩ and CD1d ϩ antigen presenting cell. The responding T cells secreted both interleukin (IL)-4 and interferon-␥ , in some cases IL-10 and transforming growth factor-␤ , and could provide help for immunoglobulin E (IgE) production. Responses to pollen phospholipids were maximally evident in blood samples obtained from allergic subjects during pollinating season, uniformly absent in Mycobacterium tuberculosis -exposed health care workers, but occasionally seen in nonallergic subjects. Finally, allergic, but not normal subjects, displayed circulating specific IgE and cutaneous weal and flare reactions to phospholipids.

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Section: Articlesupporting

confidence: 92%

Human CD1-restricted T-cell recognition of lipids from pollens

Spinozzi¹,

Agea²,

Corazzi³

et al. 2002

Journal of Allergy and Clinical Immunology

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“…Several lines of evidence suggest a role for CD1c and CD1c self-reactive T cells in human autoinflammatory and autoimmune diseases. For example, CD1c self-reactive T cells were found to be elevated in autoimmune thyroid tissues and in systemic lupus erythematosus (SLE) (23,24). In SLE, these cells induce Ig class switching to IgG and increase Ig secretion in CD1c+ B cells (24).…”

Section: Discussionmentioning

confidence: 99%

“…For example, CD1c self-reactive T cells were found to be elevated in autoimmune thyroid tissues and in systemic lupus erythematosus (SLE) (23,24). In SLE, these cells induce Ig class switching to IgG and increase Ig secretion in CD1c+ B cells (24). Conversely, CD1c high myeloid dendritic cells (CD1c+mDC) infiltrate inflamed tissues in different autoimmune conditions, including, for example, rheumatoid arthritis (RA), vitiligo, or autoimmune thyroiditis (23,25,26).…”

Section: Discussionmentioning

confidence: 99%

Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells

Mansour

Tocheva

Cave-Ayland

et al. 2016

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

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Cluster of differentiation 1c (CD1c)-dependent self-reactive T cells are abundant in human blood, but self-antigens presented by CD1c to the T-cell receptors of these cells are poorly understood. Here we present a crystal structure of CD1c determined at 2.4 Å revealing an extended ligand binding potential of the antigen groove and a substantially different conformation compared with known CD1c structures. Computational simulations exploring different occupancy states of the groove reenacted these different CD1c conformations and suggested cholesteryl esters (CE) and acylated steryl glycosides (ASG) as new ligand classes for CD1c. Confirming this, we show that binding of CE and ASG to CD1c enables the binding of human CD1c self-reactive T-cell receptors. Hence, human CD1c adopts different conformations dependent on ligand occupancy of its groove, with CE and ASG stabilizing CD1c conformations that provide a footprint for binding of CD1c self-reactive T-cell receptors.CD1 | lipid antigen | antigen presentation | T cell | cholesteryl ester C luster of differentiation 1 (CD1) proteins are a family of MHC class I-like glycoproteins that present lipid antigens to T cells. CD1 restricted T cells are abundant in humans and play important roles in host defense and immune regulation. Human CD1 proteins comprise five CD1 isoforms, CD1a, CD1b, CD1c, CD1d, and CD1e, which exhibit different intracellular trafficking behaviors and ligand binding preferences (1). Structurally, the main differences between these CD1 isoforms lie in the architecture of their lipophilic ligand binding grooves. Whereas all CD1 isoforms share a highly conserved A′ channel (or pocket) for binding C18-C26 acyl chains, specialization is provided by further connecting channels (2-7). In CD1a, the A′ channel is "fused" to a wide and shallow F′ channel, enabling binding of lipopeptides such as mycobacterial didehydroxymycobactin (DDM) (8). CD1b features a unique T′ tunnel that connects A′ and F′, thereby forming a "superchannel" for accommodating very long acyl chains (e.g., mycobacterial mycolates) (2, 4). CD1d, the only isoform also conserved in rodents, exhibits a twobranched ligand binding groove with two linear channels A′ and F′ connected near the main portal into the groove, known as the F′ portal. A similar two-branched arrangement of A′ and F′ is seen in CD1e, the only CD1 isoform not expressed on the cell surface. Compared with CD1d, CD1a, and CD1b, the portal into the groove in CD1e is widely exposed, consistent with its known role in lipid transfer processes inside lysosomes (6).CD1c presents foreign-(9, 10) as well as self-lipid antigens to T cells (11). Two recent crystal structures of human CD1c revealed a two-branched design similar to that of CD1d and CD1e, with two channels A′ and F′ connecting near the groove portal. In these structures, a mycobacterial phosphomycoketide (PM) or mannosyl-β1-phosphomycoketide (MPM) occupied the A′ channel, whereas an undefined short ligand was present in the F′ channel (7, 12). The spatial arrangement of...

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“…Goodrum et al [88] used whole peripheral blood monocytes from freshly donated normal human blood, with which it was shown that CD4 single positive T cells proliferated strongest, Sieling et al [90] reported that CD4/CD8 double negative T cells from auto-immune systemic lupus erythematosus (SLE) patients induced antibody isotype switching from IgM to IgG in a anti-cholesterol antibody activity in TB patient sera. How this may relate to the establishment of TB is discussed in more detail below.…”

Section: Does Structure Matter?mentioning

confidence: 99%

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

Verschoor

Baird

Grooten

2012

Progress in Lipid Research

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Mycolic acids constitute the waxy layer of the outer cell wall of Mycobacterium spp and a few other genera. They are diverse in structure, providing a unique chromatographic foot-print for almost each of the more than seventy Mycobacterium species. Although mainly esterified to cell wall arabinogalactan, trehalose or glucose, some free mycolic acid is secreted during in vitro growth of M. tuberculosis. In M. tuberculosis, alpha-, keto-and methoxy-mycolic acids are the main classes, each differing in their ability to attract neutrophils, induce foamy macrophages or adopt an antigenic structure for antibody recognition. Of interest is their particular relationship to cholesterol, discovered by their ability to attract cholesterol, to bind Amphotericin B or to be recognised by monoclonal antibodies that cross-react with cholesterol. The structural elements that determine this diverse functionality include the carboxylic acid in the mycolic motif, as well as the nature and stereochemistry of the two functional groups in the merochain. The functional diversity of mycolic acid classes implies that much information may be contained in the selective expression and secretion of mycolic acids to establish tuberculosis after infection of the host. Their cholesteroid nature may relate to how they utilize host cholesterol for their persistent survival.

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

Cited by 115 publications

References 55 publications

Human CD1-restricted T-cell recognition of lipids from pollens

Human CD1-restricted T-cell recognition of lipids from pollens

Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

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