Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria

Kinjo, Yuki; Illarionov, Petr A.; Vela, José Luis; Peng, Bo; Gottardi, Enrico; Li, Xiangming; Li, Yali; Imamura, Masakazu; Kaneko, Yukihiro; Okawara, Akiko; Miyazaki, Yoshitsugu; Gómez‐Velasco, Anaximandro; Rogers, Paul; Dahesh, Samira; Uchiyama, Satoshi; Khurana, Archana; Kawahara, Kazuyoshi; Yeşilkaya, Hasan; Andrew, Peter W.; Wong, Chi Huey; Kawakami, Kazuyoshi; Nizet, Victor; Besra, Gurdyal S.; Tsuji, Moriya; Zajonc, Dirk M.; Kronenberg, Mitchell

doi:10.1038/ni.2096

Cited by 300 publications

(392 citation statements)

References 40 publications

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“…The difference also raises the question whether murine iNKT and human MAIT cells perform similar effector functions. MAIT and iNKT cells are activated by Ags presented by distinct Ag-presenting molecules (4,14), and although they were shown to be activated during bacterial infections (4,14), their cytokine production can differ. Murine iNKT cells can produce Th1 and Th17 cytokines, as well as IL-4, IL-10, and IL-13 (38).…”

Section: Discussionmentioning

confidence: 99%

“…These cells patrol the murine liver sinusoids where they represent ∼20% of resident lymphocytes and can release proinflammatory cytokines (2,3). iNKT cells recognize glycolipid Ags presented by the nonpolymorphic CD1d molecule (4) and play an important role in the pathogenesis with different etiologies (5)(6)(7)(8). However, in humans, the identity of intrahepatic T cells expressing NK markers is controversial (1,2,9).…”

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confidence: 99%

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IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

Tang

Tan

et al. 2013

The Journal of Immunology

303

408

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Human mucosal-associated invariant T (MAIT) cells are a T cell population characterized by the expression of a semi-invariant TCR capable of recognizing bacterial products in the context of MR1. MAIT cells are enriched in the human liver, which is constantly exposed to bacterial products from the intestine. Whether this specific parenchymal localization influences their function remains unknown. We analyzed MAIT cells resident in the vascular bed of livers and showed that they represented the majority of T cells expressing NK markers and the dominant IL-17A+ T cell subset in the human liver sinusoids. In comparison with MAIT cells purified from peripheral blood, intrasinusoidal MAIT cells expressed markers of T cell activation; however, TCR-mediated cytokine production was equally suppressed in both circulating and intrasinusoidal MAIT cells. MAIT cells also expressed high levels of IL-7R, and we showed that IL-7, a cytokine produced by hepatocytes during inflammation, regulated TCR-mediated activation of MAIT cells, licensing them to dramatically increase Th1 cytokines and IL-17A production. Our quantitative and functional data indicate that MAIT cells are a specialized cell population highly adapted to exert their immune functions in the vascular network of the liver.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

Tang

Tan

et al. 2013

The Journal of Immunology

303

408

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“…Natural antigenic glycolipids have been detected from various foreign sources, including nonpathogenic α-proteobacteria (6)(7)(8), spirochetes (9), and other microbes, such as Streptococcus pneumoniae (10) and Bacteroides fragilis (11,12). These known microbial lipid antigens for iNKT cells share a key biochemical feature, namely an α-anomeric linkage of one hexose sugar to the lipid backbone.…”

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confidence: 99%

Structural determination of lipid antigens captured at the CD1d–T-cell receptor interface

Brennan

Cheng

Pellicci

et al. 2017

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

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Glycolipid antigens recognized by αβ T-cell receptors (TCRs) drive the activation of invariant natural killer T (iNKT) cells, a specialized subset of innate T lymphocytes. Glycolipids with α-linked anomeric carbohydrates have been identified as potent microbial lipid antigens for iNKT cells, and their unusual α-anomeric linkage has been thought to define a “foreign” lipid antigen motif. However, mammals use endogenous lipids to select iNKT cells, and there is compelling evidence for iNKT cell responses in various types of sterile inflammation. The nature of endogenous or environmental lipid antigens encountered by iNKT cells is not well defined. Here, we sought to identify lipid antigens in cow’s milk, a prominent part of the human diet. We developed a method to directly capture lipid antigens within CD1d–lipid–TCR complexes, while excluding CD1d bound to nonantigenic lipids, followed by direct biochemical analysis of the lipid antigens trapped at the TCR–CD1d interface. The specific antigens captured by this “TCR trap” method were identified as α-linked monohexosylceramides by mass spectrometry fragmentation patterns that distinguished α- from β-anomeric monohexosylceramides. These data provide direct biochemical evidence for α-linked lipid antigens from a common dietary source.

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“…The semi-invariant TCR recognizes CD1d [14], a member of the CD1 family of nonpolymorphic, MHC-I-like lipid Ag presenting molecules that is expressed on monocytes, DCs, B cells, and some nonhematopoietic cells (reviewed in [15]). Essentially all iNKT cells recognize the synthetic glycosphingolipid Ag αgalactosylceramide (αGalCer) presented by CD1d [3], and also respond variably to other glycolipids from various infectious pathogens, such as Sphingomonas; Borrelia burgdorferi, Streptococcus pneumoniae, Aspergillus fumigatus [16][17][18]. In addition, iNKT cells are strongly autoreactive against endogenous glycosphingolipids and lysophospholipids that are upregulated in cells under stress conditions [19].…”

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confidence: 99%

iNKT‐cell help to B cells: A cooperative job between innate and adaptive immune responses

2014

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T-cell help to B lymphocytes is one of the most important events in adaptive immune responses in health and disease. It is generally delivered by cognate CD4 + T follicular helper (T FH ) cells via both cell-to-cell contacts and soluble mediators, and it is essential for both the clonal expansion of antibody (Ab)-secreting B cells and memory B-cell formation. CD1d-restricted invariant natural killer T (iNKT) cells are a subset of innate-like T lymphocytes that rapidly respond to stimulation with specific lipid antigens (Ags) that are derived from infectious pathogens or stressed host cells. Activated iNKT cells produce a wide range of cytokines and upregulate costimulatory molecules that can promote activation of dendritic cells (DCs), natural killer (NK) cells, and T cells. A decade ago, we discovered that iNKT cells can help B cells to proliferate and to produce IgG Abs in vitro and in vivo. This adjuvant-like function of Ag-activated iNKT cells provides a flexible set of helper mechanisms that expand the current paradigm of T-cell-B-cell interaction and highlights the potential of iNKT-cell targeting vaccine formulations.Keywords: B-cell help r CD1d r T follicular helper cells r vaccines IntroductionThe production of neutralizing antibodies (Abs) by B cells represents a major parameter of host defense against infectious pathogens and is a key component of protective immune responses elicited by vaccines [1]. The innate and adaptive arms of the immune system are functionally separated, but seem to be highly coordinated to ensure an optimal outcome of immune responses. Although innate and adaptive immune cells are endowed with very distinct functions and timing of response, there are specialized lymphocyte subsets that straddle the two programs, and these cells have been defined as innate-like lymphocytes [2]. CD1d-rectricted invariant Vα14 natural killer T (iNKT) cells are one of the best characterized types of innate-like T lymphocytes, which display multiple effector functions upon activation [3]. Here, we review the mechanisms through which iNKT cells help B cells to promote Ab production and memory formation.Correspondence: Dr. Paolo Dellabona e-mail: dellabona.paolo@hsr.itThe TD and TI paradigm of the B-cell response B-cell responses are generally described as T-dependent (TD) or T-independent (TI), based on the requirement for T-cell help for Ab production. TD responses are induced by protein antigens (Ags) that are recognized by specific B cells in the presence of cognate T-cell help, which is provided by a specialized subset of CD4 + T helper (Th) cells called T follicular helper (T FH ) cells [4]. Ags reach the follicles, the B-cell zone of secondary lymphoid organs, and activate B cells upon binding to the specific B-cell receptors (BCRs [5]). This leads to Ag internalization, presentation of the processed Ag peptides into MHC class II (MHC II) molecules, and migration of the activated B cells to the border of the T-B-cell zone [4]. T FH cells are induced in the T-cell zone by dendritic cells (DCs) t...

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Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria

Cited by 300 publications

References 40 publications

IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

Structural determination of lipid antigens captured at the CD1d–T-cell receptor interface

iNKT‐cell help to B cells: A cooperative job between innate and adaptive immune responses

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