<scp>ER</scp>
            stress in antigen‐presenting cells promotes
            <scp>NKT</scp>
            cell activation through endogenous neutral lipids

Govindarajan, Srinath; Verheugen, Eveline; Venken, Koen; Gaublomme, Djoere; Maelegheer, Margaux; Cloots, Eva; Gysens, Fien; Geest, Bruno G. De; Cheng, Tan-Yun; Moody, D. Branch; Janssens, Sophie; Drennan, Michael

doi:10.15252/embr.201948927

Cited by 26 publications

(30 citation statements)

References 76 publications

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“…Furthermore, the CD1-restricted TCRs of NKT cells are autoreactive to CD1 expressing APCs ( Cardell et al., 1995 ; Skold et al., 2003 ; Almeida et al., 2019 ). Indeed, endoplasmic reticulum (ER) stress in APCs is a potent inducer of CD1d-dependent NKT cell auto-reactivity ( Govindarajan et al., 2020 ).…”

Section: Nkt Cell Antigensmentioning

confidence: 99%

NKT Cells Contribute to the Control of Microbial Infections

Vogt

Mattner

2021

Front. Cell. Infect. Microbiol.

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Innate (-like) T lymphocytes such as natural killer T (NKT) cells play a pivotal role in the recognition of microbial infections and their subsequent elimination. They frequently localize to potential sites of pathogen entry at which they survey extracellular and intracellular tissue spaces for microbial antigens. Engagement of their T cell receptors (TCRs) induces an explosive release of different cytokines and chemokines, which often pre-exist as constitutively expressed gene transcripts in NKT cells and underlie their poised effector state. Thus, NKT cells regulate immune cell migration and activation and subsequently, bridge innate and adaptive immune responses. In contrast to conventional T cells, which react to peptide antigens, NKT cells recognize lipids presented by the MHC class I like CD1d molecule on antigen presenting cells (APCs). Furthermore, each NKT cell TCR can recognize various antigen specificities, whereas a conventional T lymphocyte TCR reacts mostly only to one single antigen. These lipid antigens are either intermediates of the intracellular APC`s-own metabolism or originate from the cell wall of different bacteria, fungi or protozoan parasites. The best-characterized subset, the type 1 NKT cell subset expresses a semi-invariant TCR. In contrast, the TCR repertoire of type 2 NKT cells is diverse. Furthermore, NKT cells express a panoply of inhibitory and activating NK cell receptors (NKRs) that contribute to their primarily TCR-mediated rapid, innate like immune activation and even allow an adaption of their immune response in an adoptive like manner. Dueto their primary localization at host-environment interfaces, NKT cells are one of the first immune cells that interact with signals from different microbial pathogens. Vice versa, the mutual exchange with local commensal microbiota shapes also the biology of NKT cells, predominantly in the gastrointestinal tract. Following infection, two main signals drive the activation of NKT cells: first, cognate activation upon TCR ligation by microbial or endogenous lipid antigens; and second, bystander activation due to cytokines. Here we will discuss the role of NKT cells in the control of different microbial infections comparing pathogens expressing lipid ligands in their cell walls to infectious agents inducing endogenous lipid antigen presentation by APCs.

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Section: Nkt Cell Antigensmentioning

confidence: 99%

NKT Cells Contribute to the Control of Microbial Infections

Vogt

Mattner

2021

Front. Cell. Infect. Microbiol.

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“…Additionally, ER stress decreased the expression of CD1d in hepatocytes, contributing to NKT cell dysregulation in fatty livers (140). However, ER stress in macrophages potently induced CD1d-dependent iNKT cell autoreactivity via IRE1α/PERK pathways, since macrophages undergoing ER stress generated the neutral lipids that were enriched and loaded onto CD1d to activate iNKT cells (141). HFD-enhanced ER stress in adipocytes suppressed Th2 cytokine expression, which modulated adipose tissue macrophage polarization toward M1 and mediated systemic insulin resistance (142).…”

Section: Lipotoxicitymentioning

confidence: 99%

Roles of Hepatic Innate and Innate-Like Lymphocytes in Nonalcoholic Steatohepatitis

Chen

Tian

2020

Front. Immunol.

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Nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease (NAFLD), is accompanied by steatosis, hepatocyte injury and liver inflammation, which has been a health problem in the world as one of the major high risk factors of cirrhosis and hepatocellular carcinoma (HCC). Complex immune responses involving T cells, B cells, Kupffer cells, monocytes, neutrophils, DCs and other innate lymphocytes account for the pathogenesis of NASH; however, the underlying mechanisms have not been clearly elucidated in detail. In the liver, innate and innate-like lymphocytes account for more than two-thirds of total lymphocytes and play an important role in maintaining the immune homeostasis. Therefore, their roles in the progression of NASH deserves investigation. In this review, we summarized murine NASH models for immunological studies, including the diet-induced NASH, chemical-induced NASH and genetic-induced NASH. The role of innate and innate-like lymphocytes including NK cells, ILCs, NKT, γδT and MAIT cells in the progression of NASH were elucidated. Further, the metabolic regulation of the innate immune response was addressed in consideration to explain the molecular mechanisms. Based on the findings of the reviewed studies, strategies of immune intervention are proposed to control the progression of NASH.

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“…In contrast to the pro-inflammatory effect of PA in macrophages, a recent study found that PA enhanced the degradation of RIDD on T-bet and gata-3 mRNA by inducing ER stress in iNKT cells, thereby suppressing the production of IL-4 and IFN-γ and attenuating arthritis ( Ko et al, 2017 ). In addition, ER stress induced IRE1α and PERK-dependent branches can increase lipid antigens bound to CD1d molecules, thereby enhancing iNKT cell activation ( Bedard et al, 2019 ; Govindarajan et al, 2020 ). This indicates that ER-stressed APCs can affect iNKT cell activation via CD1d.…”

Section: Endoplasmic Reticulum Quality Control and Immune Cellsmentioning

confidence: 99%

Endoplasmic Reticulum Quality Control in Immune Cells

Jiang

Tao

Chen

et al. 2021

Front. Cell Dev. Biol.

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The endoplasmic reticulum quality control (ERQC) system, including endoplasmic reticulum-associated degradation (ERAD), the unfolded protein response (UPR), and autophagy, presides over cellular protein secretion and maintains proteostasis in mammalian cells. As part of the immune system, a variety of proteins are synthesized and assembled correctly for the development, activation, and differentiation of immune cells, such as dendritic cells (DCs), macrophages, myeloid-derived-suppressor cells (MDSCs), B lymphocytes, T lymphocytes, and natural killer (NK) cells. In this review, we emphasize the role of the ERQC in these immune cells, and also discuss how the imbalance of ER homeostasis affects the immune response, thereby suggesting new therapeutic targets for immunotherapy.

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ER stress in antigen‐presenting cells promotes NKT cell activation through endogenous neutral lipids

Cited by 26 publications

References 76 publications

NKT Cells Contribute to the Control of Microbial Infections

NKT Cells Contribute to the Control of Microbial Infections

Roles of Hepatic Innate and Innate-Like Lymphocytes in Nonalcoholic Steatohepatitis

Endoplasmic Reticulum Quality Control in Immune Cells

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