CD1d function is regulated by microsomal triglyceride transfer protein

Brozović, Suzana; Nagaishi, Takashi; Yoshida, Masaru; Betz, Stephan Christian; Salas, Antonio; Chen, Daohong; Kaser, Arthur; Glickman, Jonathan N.; Kuo, Timothy; Little, Alicia J.; Morrison, Jamin; Corazza, Nadia; Kim, Jin Yong; Colgan, Sean P.; Young, Stephen G.; Exley, Mark A.; Blumberg, Richard S.

doi:10.1038/nm1043

Cited by 161 publications

(168 citation statements)

References 29 publications

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“…However, some of the reported functional consequences of the genetic ablation or chemical inhibition of MTP were not fully consistent with this proposed function. For example, the decrease in CD1d surface expression was often modest and could not alone explain the profound defects in lipid antigen presentation seen upon genetic ablation of mttp (14). Likewise, chemical inhibition of MTP in two diff erent human cell lines led to a defect in NKT cell stimulation without notable decrease in surface CD1d levels (13).…”

Section: Discussionmentioning

confidence: 99%

“…In the absence of MTP, misfolded CD1d molecules would be retained in the ER, explaining the reduction of surface CD1d and the impaired antigen presentation observed in MTP-defi cient cells. Consistent with this hypothesis, MTP ablation after injection of double-stranded RNA (dsRNA [polyI:C]) in mttp fl /fl Mx1-Cre mice aff orded resistance to diseases mediated by CD1d-restricted NKT cells such as αGalCer-induced hepatitis and oxazolone-induced colitis (14).…”

mentioning

confidence: 87%

“…MTP was originally characterized as a heterodimer of protein disulfi de isomerase and a 97-kD subunit in the ER of hepatocytes and enterocytes (10)(11)(12), but recent studies have demonstrated weak expression in hemopoietic cells as well, including T cells and dendritic cells (13). Because MTP coprecipitated with CD1d and could transfer lipids onto plate-bound CD1d in a cell-free assay, it was proposed that MTP might assist in loading lipids onto CD1 molecules during biosynthesis in the ER in a manner similar to chaperone-assisted loading of peptides onto nascent MHC class I molecules (13,14). In the absence of MTP, misfolded CD1d molecules would be retained in the ER, explaining the reduction of surface CD1d and the impaired antigen presentation observed in MTP-defi cient cells.…”

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confidence: 99%

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A distal effect of microsomal triglyceride transfer protein deficiency on the lysosomal recycling of CD1d

Sagiv¹,

Bai²,

Wei³

et al. 2007

J Cell Biol

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Microsomal triglyceride transfer protein (MTP) is an endoplasmic reticulum (ER)-residentlipid transfer protein involved in the biosynthesis and lipid loading of apolipoprotein B. MTP was recently suggested to directly regulate the biosynthesis of the MHC I-like, lipid antigen presenting molecule CD1d, based on coprecipitation experiments and lipid loading assays. However, we found that the major impact of MTP defi ciency occurred distal to the ER and Golgi compartments. Thus, although the rates of CD1d biosynthesis, glycosylation maturation, and internalization from the cell surface were preserved, the late but essential stage of recycling from lysosome to plasma membrane was profoundly impaired. Likewise, functional experiments indicated defects of CD1d-mediated lipid presentation in the lysosome but not in the secretory pathway. These intriguing fi ndings suggest a novel, unexpected role of MTP at a late stage of CD1d traffi cking in the lysosomal compartment.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 87%

mentioning

confidence: 99%

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A distal effect of microsomal triglyceride transfer protein deficiency on the lysosomal recycling of CD1d

Sagiv¹,

Bai²,

Wei³

et al. 2007

J Cell Biol

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Section: Trafficking Of Cd1 Molecules and Antigen Loading In Differenmentioning

confidence: 99%

“…A second issue is how PC moves from the ER membrane into nascent CD1b and CD1d molecules. The ER-resident microsomal triglyceride transfer protein has been suggested as a key player in this process [39,40], in addition to having an important role in CD1d recycling from Ly to plasma membrane [41].Properly assembled CD1 molecules move from the ER to the Golgi, where their glycosylation is completed. CD1a forms supercomplexes with MHC class II molecules and the invariant chain and traffics to the plasma membrane where it localizes within detergent-resistant membrane regions together with CD9 [42].…”

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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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CD1d ‐Restricted Natural Killer T Cells

Hill

Bezbradica

Kaer

et al. 2016

Encyclopedia of Life Sciences

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Natural killer T (NKT) cells that express the semi‐invariant T‐cell receptor are innate‐like lymphocytes whose functions are controlled by self and foreign glycolipid ligands. Such ligands are presented by the antigen‐presenting, MHC class I‐like molecule CD1d, which belongs to a family of lipid antigen‐presenting molecules collectively called CD1. Activation of NKT cells in vivo results in rapid release of copious amounts of effector cytokines and chemokines with which they regulate innate and adaptive immune responses to pathogens, certain types of cancers and self‐antigens. The nature of CD1d‐restricted ligands, the manners in which they are recognised and the unique effector functions of NKT cells suggest an immunoregulatory role for this T‐cell subset. Their ability to respond fast and our ability to steer NKT cell cytokine responses to altered lipid ligands make them an important target for vaccine design and immunotherapies against autoimmune diseases. This article summarises our current understanding of CD1d‐restricted NKT cell biology and how these innate‐like lymphocytes control inflammation. Key Concepts CD1d molecules belong to a family of lipid antigen‐presenting molecules collectively called CD1. CD1d molecules resemble peptide antigen‐presenting MHC class I molecules. CD1d molecules restrict the specificity and functions of Natural killer T (NKT) cells. NKT cells recognise self‐ and nonself‐lipid ligands. Antigen recognition quickly activates NKT cells, which respond immediately by releasing proinflammatory and immunoregulatory cytokines and chemokines. Activated NKT cells communicate with cells of the innate and adaptive immune systems by cell–cell interactions and/or via soluble mediators. Such communications allow NKT cells to control immune responses to microbial pathogens and certain cancers. NKT‐cell activation has beneficial and, sometimes, adverse effects on certain autoimmune and metabolic disorders. NKT cells are targets for vaccine adjuvants and immunotherapies.

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CD1d function is regulated by microsomal triglyceride transfer protein

Cited by 161 publications

References 29 publications

A distal effect of microsomal triglyceride transfer protein deficiency on the lysosomal recycling of CD1d

A distal effect of microsomal triglyceride transfer protein deficiency on the lysosomal recycling of CD1d

The cellular and biochemical rules of lipid antigen presentation

CD1d ‐Restricted Natural Killer T Cells

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