Publications by authors named "Yannick Simoni"

27 Publications

  • Page 1 of 1

Human Tumor-Infiltrating MAIT Cells Display Hallmarks of Bacterial Antigen Recognition in Colorectal Cancer.

Cell Rep Med 2020 Jun 23;1(3):100039. Epub 2020 Jun 23.

Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Growing evidence indicates a role for the gut microbiota in modulating anti-tumor treatment efficacy in human cancer. Here we study mucosa-associated invariant T (MAIT) cells to look for evidence of bacterial antigen recognition in human colon, lung, and kidney carcinomas. Using mass cytometry and single-cell mRNA sequencing, we identify a tumor-infiltrating MAIT cell subset expressing CD4 and Foxp3 and observe high expression of CD39 on MAIT cells from colorectal cancer (CRC) only, which we show to be expressed specifically after TCR stimulation. We further reveal that these cells are phenotypically and functionally exhausted. Sequencing data show high bacterial infiltration in CRC tumors and highlight an enriched species, with capability to activate MAIT cells in a TCR-dependent way. Our results provide evidence of a MAIT cell response to microbial antigens in CRC and could pave the way for manipulating MAIT cells or the microbiome for cancer therapy.
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http://dx.doi.org/10.1016/j.xcrm.2020.100039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659584PMC
June 2020

Partial absence of PD-1 expression by tumor-infiltrating EBV-specific CD8 T cells in EBV-driven lymphoepithelioma-like carcinoma.

Clin Transl Immunology 2020 9;9(9):e1175. Epub 2020 Sep 9.

Vaccine and Infectious Disease Division Fred Hutchinson Cancer Research Center Seattle WA USA.

Objectives: Lymphoepithelioma-like carcinoma (LELC) is an uncommon lung cancer, typically observed in young, non-smoking Asian populations. LELC is associated with Epstein-Barr virus (EBV) infection of lung tumor cells of epithelial origin, suggesting a carcinogenic role of EBV as observed in nasopharyngeal carcinoma (NPC). Here, we studied the antigen specificity and phenotype of EBV-specific CD8 T cells in blood and tumor of one LELC patient positive for EBV infection in lung tumor cells.

Methods: Using multiplex MHC class I tetramers, mass cytometry and mRNA sequencing, we studied EBV-specific CD8 T cells at the transcriptomic and phenotypic levels in blood and tumor tissues of the LELC patient.

Results: Lymphoepithelioma-like carcinoma lung tumor cells were positive for EBV infection. In both blood and tumor tissues, we detected two populations of EBV-specific CD8 T cells targeting the EBV lytic cycle proteins: BRLF1 and BMLF1. Transcriptomic analyses of these two populations in the tumor, which can be considered as tumor-specific, revealed their distinct exhausted profile and polyclonal TCR repertoire. High-dimensional phenotypical analysis revealed the distinct phenotype of these cells between blood and tumor tissues. In tumor tissue, EBV-specific CD8 TILs were phenotypically heterogeneous, but consistently expressed CD39. Unexpectedly, although the LELC tumor cells expressed abundant PD-L1, these tumor-specific CD8 tumor-infiltrating lymphocytes (TILs) mostly did not express PD-1.

Conclusion: Epstein-Barr virus-specific CD8 TILs in EBV-driven tumor are heterogeneous and partially lack PD-1 expression, suggesting that anti-PD1/PD-L1 immunotherapy may not be an appropriate strategy for disinhibiting EBV-specific cells in the treatment of LELC patients.
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http://dx.doi.org/10.1002/cti2.1175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503213PMC
September 2020

Ontogeny of different subsets of yellow fever virus-specific circulatory CXCR5 CD4 T cells after yellow fever vaccination.

Sci Rep 2020 09 24;10(1):15686. Epub 2020 Sep 24.

Benaroya Research Institute At Virginia Mason Medical Center, 1201, 9th Ave, Seattle, WA, 98101, USA.

Monitoring the frequency of circulatory CXCR5 (cCXCR5) CD4 T cells in periphery blood provides a potential biomarker to draw inferences about T follicular helper (T) activity within germinal center. However, cCXCR5 T cells are highly heterogeneous in their expression of ICOS, PD1 and CD38 and the relationship between different cCXCR5 subsets as delineated by these markers remains unclear. We applied class II tetramer reagents and mass cytometry to investigate the ontogeny of different subsets of cCXCR5 T cell following yellow fever immunization. Through unsupervised analyses of mass cytometry data, we show yellow fever virus-specific cCXCR5 T cells elicited by vaccination were initially CD38ICOSPD1, but then transitioned to become CD38ICOSPD1 and CD38ICOSPD1 before coming to rest as a CD38ICOSPD1 subset. These results imply that most antigen-specific cCXCR5 T cells, including the CD38ICOSPD1 CXCR5 T cells are derived from the CXCR5CD38ICOSPD1 subset, the subset that most resembles preT/T in the germinal center.
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http://dx.doi.org/10.1038/s41598-020-72610-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519049PMC
September 2020

Mucosal-associated invariant T cells promote inflammation and intestinal dysbiosis leading to metabolic dysfunction during obesity.

Nat Commun 2020 07 24;11(1):3755. Epub 2020 Jul 24.

Université de Paris, Institut Cochin INSERM, CNRS F-75014, Paris, France.

Obesity is associated with low-grade chronic inflammation promoting insulin-resistance and diabetes. Gut microbiota dysbiosis is a consequence as well as a driver of obesity and diabetes. Mucosal-associated invariant T cells (MAIT) are innate-like T cells expressing a semi-invariant T cell receptor restricted to the non-classical MHC class I molecule MR1 presenting bacterial ligands. Here we show that during obesity MAIT cells promote inflammation in both adipose tissue and ileum, leading to insulin resistance and impaired glucose and lipid metabolism. MAIT cells act in adipose tissue by inducing M1 macrophage polarization in an MR1-dependent manner and in the gut by inducing microbiota dysbiosis and loss of gut integrity. Both MAIT cell-induced tissue alterations contribute to metabolic dysfunction. Treatment with MAIT cell inhibitory ligand demonstrates its potential as a strategy against inflammation, dysbiosis and metabolic disorders.
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http://dx.doi.org/10.1038/s41467-020-17307-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381641PMC
July 2020

A Targeted Multi-omic Analysis Approach Measures Protein Expression and Low-Abundance Transcripts on the Single-Cell Level.

Cell Rep 2020 04;31(1):107499

Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, WA 98109, USA; Department of Global Health and Department of Immunology, University of Washington, Seattle, WA 98195, USA. Electronic address:

High-throughput single-cell RNA sequencing (scRNA-seq) has become a frequently used tool to assess immune cell heterogeneity. Recently, the combined measurement of RNA and protein expression was developed, commonly known as cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq). Acquisition of protein expression data along with transcriptome data resolves some of the limitations inherent to only assessing transcripts but also nearly doubles the sequencing read depth required per single cell. Furthermore, there is still a paucity of analysis tools to visualize combined transcript-protein datasets. Here, we describe a targeted transcriptomics approach that combines an analysis of over 400 genes with simultaneous measurement of over 40 proteins on 2 × 10 cells in a single experiment. This targeted approach requires only about one-tenth of the read depth compared to a whole-transcriptome approach while retaining high sensitivity for low abundance transcripts. To analyze these multi-omic datasets, we adapted one-dimensional soli expression by nonlinear stochastic embedding (One-SENSE) for intuitive visualization of protein-transcript relationships on a single-cell level.
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http://dx.doi.org/10.1016/j.celrep.2020.03.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224638PMC
April 2020

Multiplex MHC Class I Tetramer Combined with Intranuclear Staining by Mass Cytometry.

Methods Mol Biol 2019 ;1989:147-158

Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), Singapore, Singapore.

Antigen-specific CD8 T cells play a crucial role in the host protective immune response against viruses, tumors, and other diseases. Major histocompatibility complex (MHC) class I tetramers allow for a direct detection of such antigen-specific CD8 T cells. Using mass cytometry together with multiplex MHC class I tetramer staining, we are able to screen more than 1000 different antigen candidates simultaneously across tissues in health and disease, while retaining the possibility to deliver an in-depth characterization of antigen-specific CD8 T cells and associated phenotypes. Here we describe the method for a MHC class I tetramer multiplexing approach together with intracellular antibody staining for a parallel phenotypic cell characterization using mass cytometry in human specimens.
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http://dx.doi.org/10.1007/978-1-4939-9454-0_11DOI Listing
March 2020

A Subset of Type I Conventional Dendritic Cells Controls Cutaneous Bacterial Infections through VEGFα-Mediated Recruitment of Neutrophils.

Immunity 2019 04 27;50(4):1069-1083.e8. Epub 2019 Mar 27.

Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Biopolis, Singapore 138648, Singapore; Skin Research Institute of Singapore (SRIS), Agency for Science, Technology and Research (A(∗)STAR), 11 Mandalay Rd., Singapore 308232, Singapore. Electronic address:

Skin conventional dendritic cells (cDCs) exist as two distinct subsets, cDC1s and cDC2s, which maintain the balance of immunity to pathogens and tolerance to self and microbiota. Here, we examined the roles of dermal cDC1s and cDC2s during bacterial infection, notably Propionibacterium acnes (P. acnes). cDC1s, but not cDC2s, regulated the magnitude of the immune response to P. acnes in the murine dermis by controlling neutrophil recruitment to the inflamed site and survival and function therein. Single-cell mRNA sequencing revealed that this regulation relied on secretion of the cytokine vascular endothelial growth factor α (VEGF-α) by a minor subset of activated EpCAMCD59Ly-6D cDC1s. Neutrophil recruitment by dermal cDC1s was also observed during S. aureus, bacillus Calmette-Guérin (BCG), or E. coli infection, as well as in a model of bacterial insult in human skin. Thus, skin cDC1s are essential regulators of the innate response in cutaneous immunity and have roles beyond classical antigen presentation.
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http://dx.doi.org/10.1016/j.immuni.2019.03.001DOI Listing
April 2019

[Identification of tumor-specific CD8 T cells with a surface marker].

Med Sci (Paris) 2018 12 9;34(12):1032-1034. Epub 2019 Jan 9.

Singapore Immunology Network (SIgN), Agency for science, technology and research, 8A Biomedical Grove, 138648 Singapour.

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http://dx.doi.org/10.1051/medsci/2018286DOI Listing
December 2018

Mapping of γ/δ T cells reveals Vδ2+ T cells resistance to senescence.

EBioMedicine 2019 Jan 7;39:44-58. Epub 2018 Dec 7.

Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Immunos Building, Singapore 138648, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore; Department of Microbiology, National University of Singapore, Singapore, Singapore; Department of Biology, Faculty of Science, University Tunis El Manar, Tunis, Tunisia. Electronic address:

Background: Immune adaptation with aging is a major of health outcomes. Studies in humans have mainly focus on αβ T cells while γδ T cells have been neglected despite their role in immunosurveillance. We investigated the impact of aging on γδ T cell subsets phenotypes, functions, senescence and their molecular response to stress.

Methods: Peripheral blood of young and old donors in Singapore have been used to assess the phenotype, functional capacity, proliferation capacity and gene expression of the various γδ T cell subsets. Peripheral blood mononuclear cells from apheresis cones and young donors have been used to characterize the telomere length, epigenetics profile and DNA damage response of the various γδ T cell subsets phenotype.

Findings: Our data shows that peripheral Vδ2+ phenotype, functional capacity (cytokines, cytotoxicity, proliferation) and gene expression profile are specific when compared against all other αβ and γδ T cells in aging. Hallmarks of senescence including telomere length, epigenetic profile and DNA damage response of Vδ2+ also differs against all other αβ and γδ T cells.

Interpretation: Our results highlight the differential impact of lifelong stress on γδ T cells subsets, and highlight possible mechanisms that enable Vδ2+ to be resistant to cellular aging. The new findings reinforce the concept that Vδ2+ have an "innate-like" behavior and are more resilient to the environment as compared to "adaptive-like" Vδ1+ T cells.
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http://dx.doi.org/10.1016/j.ebiom.2018.11.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354624PMC
January 2019

Reverse-engineering flow-cytometry gating strategies for phenotypic labelling and high-performance cell sorting.

Bioinformatics 2019 01;35(2):301-308

Singapore Immunology Network, Agency for Science Technology and Research, Singapore.

Motivation: Recent flow and mass cytometers generate datasets of dimensions 20 to 40 and a million single cells. From these, many tools facilitate the discovery of new cell populations associated with diseases or physiology. These new cell populations require the identification of new gating strategies, but gating strategies become exponentially more difficult to optimize when dimensionality increases. To facilitate this step, we developed Hypergate, an algorithm which given a cell population of interest identifies a gating strategy optimized for high yield and purity.

Results: Hypergate achieves higher yield and purity than human experts, Support Vector Machines and Random-Forests on public datasets. We use it to revisit some established gating strategies for the identification of innate lymphoid cells, which identifies concise and efficient strategies that allow gating these cells with fewer parameters but higher yield and purity than the current standards. For phenotypic description, Hypergate's outputs are consistent with fields' knowledge and sparser than those from a competing method.

Availability And Implementation: Hypergate is implemented in R and available on CRAN. The source code is published at http://github.com/ebecht/hypergate under an Open Source Initiative-compliant licence.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/bty491DOI Listing
January 2019

Bystander CD8 T cells are abundant and phenotypically distinct in human tumour infiltrates.

Nature 2018 05 16;557(7706):575-579. Epub 2018 May 16.

Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), Singapore, Singapore.

Various forms of immunotherapy, such as checkpoint blockade immunotherapy, are proving to be effective at restoring T cell-mediated immune responses that can lead to marked and sustained clinical responses, but only in some patients and cancer types. Patients and tumours may respond unpredictably to immunotherapy partly owing to heterogeneity of the immune composition and phenotypic profiles of tumour-infiltrating lymphocytes (TILs) within individual tumours and between patients. Although there is evidence that tumour-mutation-derived neoantigen-specific T cells play a role in tumour control, in most cases the antigen specificities of phenotypically diverse tumour-infiltrating T cells are largely unknown. Here we show that human lung and colorectal cancer CD8 TILs can not only be specific for tumour antigens (for example, neoantigens), but also recognize a wide range of epitopes unrelated to cancer (such as those from Epstein-Barr virus, human cytomegalovirus or influenza virus). We found that these bystander CD8 TILs have diverse phenotypes that overlap with tumour-specific cells, but lack CD39 expression. In colorectal and lung tumours, the absence of CD39 in CD8 TILs defines populations that lack hallmarks of chronic antigen stimulation at the tumour site, supporting their classification as bystanders. Expression of CD39 varied markedly between patients, with some patients having predominantly CD39 CD8 TILs. Furthermore, frequencies of CD39 expression among CD8 TILs correlated with several important clinical parameters, such as the mutation status of lung tumour epidermal growth factor receptors. Our results demonstrate that not all tumour-infiltrating T cells are specific for tumour antigens, and suggest that measuring CD39 expression could be a straightforward way to quantify or isolate bystander T cells.
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http://dx.doi.org/10.1038/s41586-018-0130-2DOI Listing
May 2018

Adaptive NKG2CCD57 Natural Killer Cell and Tim-3 Expression During Viral Infections.

Front Immunol 2018 20;9:686. Epub 2018 Apr 20.

Singapore Immunology Network (SIgN), Aging and Immunity Program, Agency for Science Technology and Research (ASTAR), Singapore, Singapore.

Repetitive stimulation by persistent pathogens such as human cytomegalovirus (HCMV) or human immunodeficiency virus (HIV) induces the differentiation of natural killer (NK) cells. This maturation pathway is characterized by the acquisition of phenotypic markers, CD2, CD57, and NKG2C, and effector functions-a process regulated by Tim-3 and orchestrated by a complex network of transcriptional factors, involving T-bet, Eomes, Zeb2, promyelocytic leukemia zinc finger protein, and Foxo3. Here, we show that persistent immune activation during chronic viral co-infections (HCMV, hepatitis C virus, and HIV) interferes with the functional phenotype of NK cells by modulating the Tim-3 pathway; a decrease in Tim-3 expression combined with the acquisition of inhibitory receptors skewed NK cells toward an exhausted and cytotoxic phenotype in an inflammatory environment during chronic HIV infection. A better understanding of the mechanisms underlying NK cell differentiation could aid the identification of new immunological targets for checkpoint blockade therapies in a manner that is relevant to chronic infection and cancer.
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http://dx.doi.org/10.3389/fimmu.2018.00686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919961PMC
June 2019

CD161 Defines a Functionally Distinct Subset of Pro-Inflammatory Natural Killer Cells.

Front Immunol 2018 9;9:486. Epub 2018 Apr 9.

The Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.

CD161 is a C-type lectin-like receptor expressed on the majority of natural killer (NK) cells; however, the significance of CD161 expression on NK cells has not been comprehensively investigated. Recently, we found that CD161 expression identifies a transcriptional and innate functional phenotype that is shared across various T cell populations. Using mass cytometry and microarray experiments, we demonstrate that this functional phenotype extends to NK cells. CD161 marks NK cells that have retained the ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. These pro-inflammatory NK cells are present in the inflamed lamina propria where they are enriched for integrin CD103 expression. Thus, CD161 expression identifies NK cells that may contribute to inflammatory disease pathogenesis and correlates with an innate responsiveness to cytokines in both T and NK cells.
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http://dx.doi.org/10.3389/fimmu.2018.00486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900032PMC
April 2019

Mass cytometry: a powerful tool for dissecting the immune landscape.

Curr Opin Immunol 2018 04 11;51:187-196. Epub 2018 Apr 11.

Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), Singapore. Electronic address:

Advancement in methodologies for single cell analysis has historically been a major driver of progress in immunology. Currently, high dimensional flow cytometry, mass cytometry and various forms of single cell sequencing-based analysis methods are being widely adopted to expose the staggering heterogeneity of immune cells in many contexts. Here, we focus on mass cytometry, a form of flow cytometry that allows for simultaneous interrogation of more than 40 different marker molecules, including cytokines and transcription factors, without the need for spectral compensation. We argue that mass cytometry occupies an important niche within the landscape of single-cell analysis platforms that enables the efficient and in-depth study of diverse immune cell subsets with an ability to zoom-in on myeloid and lymphoid compartments in various tissues in health and disease. We further discuss the unique features of mass cytometry that are favorable for combining multiplex peptide-MHC multimer technology and phenotypic characterization of antigen specific T cells. By referring to recent studies revealing the complexities of tumor immune infiltrates, we highlight the particular importance of this technology for studying cancer in the context of cancer immunotherapy. Finally, we provide thoughts on current technical limitations and how we imagine these being overcome.
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http://dx.doi.org/10.1016/j.coi.2018.03.023DOI Listing
April 2018

Activation of the Receptor Tyrosine Kinase AXL Regulates the Immune Microenvironment in Glioblastoma.

Cancer Res 2018 06 12;78(11):3002-3013. Epub 2018 Mar 12.

Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama.

Glioblastoma (GBM) is a lethal disease with no effective therapies available. We previously observed upregulation of the TAM (Tyro-3, Axl, and Mer) receptor tyrosine kinase family member AXL in mesenchymal GBM and showed that knockdown of AXL induced apoptosis of mesenchymal, but not proneural, glioma sphere cultures (GSC). In this study, we report that BGB324, a novel small molecule inhibitor of AXL, prolongs the survival of immunocompromised mice bearing GSC-derived mesenchymal GBM-like tumors. We show that protein S (PROS1), a known ligand of other TAM receptors, was secreted by tumor-associated macrophages/microglia and subsequently physically associated with and activated AXL in mesenchymal GSC. PROS1-driven phosphorylation of AXL (pAXL) induced NFκB activation in mesenchymal GSC, which was inhibited by BGB324 treatment. We also found that treatment of GSC-derived mouse GBM tumors with nivolumab, a blocking antibody against the immune checkpoint protein PD-1, increased intratumoral macrophages/microglia and activation of AXL. Combinatorial therapy with nivolumab plus BGB324 effectively prolonged the survival of mice bearing GBM tumors. Clinically, expression of AXL or PROS1 was associated with poor prognosis for patients with GBM. Our results suggest that the PROS1-AXL pathway regulates intrinsic mesenchymal signaling and the extrinsic immune microenvironment, contributing to the growth of aggressive GBM tumors. These findings suggest that development of combination treatments of AXL and immune checkpoint inhibitors may provide benefit to patients with GBM. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-2433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984695PMC
June 2018

Dissecting human ILC heterogeneity: more than just three subsets.

Immunology 2018 03 26;153(3):297-303. Epub 2017 Dec 26.

Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), Singapore.

Innate lymphoid cells (ILCs) have been divided into three distinct groups based on functional capacities, cytokine profiles and transcription factor expression. Studies performed mainly in mice have demonstrated the importance of ILCs in chronic inflammation, infection, allergy and cancer. In this review, we discuss the heterogeneity of human ILC and focus primarily on the taxonomy of human ILC cell subsets and their phenotypical and functional diversity. We summarize recent findings concerning the diversity of ILCs between and within the major subsets [natural killer (NK), ILC1, intra-epithelial ILC1 (ieILC1), ILC2, ILC3, lymphoid tissues inducer (LTi) and ILC progenitor (ILCP)], as well as the abundance of each in human tissues. We also discuss the similarities observed between groups of cells in term of receptors expressed and cytokines produced, and how these relate to the pleiotropic properties of each subset.
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http://dx.doi.org/10.1111/imm.12862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795188PMC
March 2018

Toward Meaningful Definitions of Innate-Lymphoid-Cell Subsets.

Immunity 2017 05;46(5):760-761

Agency for Science, Technology and Research (A(∗)STAR), Singapore Immunology Network (SIgN), 138648 Singapore. Electronic address:

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http://dx.doi.org/10.1016/j.immuni.2017.04.026DOI Listing
May 2017

Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency.

Immunity 2017 01 13;46(1):148-161. Epub 2016 Dec 13.

Agency for Science, Technology and Research (A(∗)STAR), Singapore Immunology Network (SIgN), 138648 Singapore. Electronic address:

Animal models have highlighted the importance of innate lymphoid cells (ILCs) in multiple immune responses. However, technical limitations have hampered adequate characterization of ILCs in humans. Here, we used mass cytometry including a broad range of surface markers and transcription factors to accurately identify and profile ILCs across healthy and inflamed tissue types. High dimensional analysis allowed for clear phenotypic delineation of ILC2 and ILC3 subsets. We were not able to detect ILC1 cells in any of the tissues assessed, however, we identified intra-epithelial (ie)ILC1-like cells that represent a broader category of NK cells in mucosal and non-mucosal pathological tissues. In addition, we have revealed the expression of phenotypic molecules that have not been previously described for ILCs. Our analysis shows that human ILCs are highly heterogeneous cell types between individuals and tissues. It also provides a global, comprehensive, and detailed description of ILC heterogeneity in humans across patients and tissues.
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http://dx.doi.org/10.1016/j.immuni.2016.11.005DOI Listing
January 2017

Innate Lymphoid Cells Are Depleted Irreversibly during Acute HIV-1 Infection in the Absence of Viral Suppression.

Immunity 2016 Feb 2;44(2):391-405. Epub 2016 Feb 2.

KwaZulu-Natal Research Institute for Tuberculosis & HIV (K-RITH), University of KwaZulu-Natal (UKZN), 4001 Durban, South Africa; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139-4307, USA.

Innate lymphoid cells (ILCs) play a central role in the response to infection by secreting cytokines crucial for immune regulation, tissue homeostasis, and repair. Although dysregulation of these systems is central to pathology, the impact of HIV-1 on ILCs remains unknown. We found that human blood ILCs were severely depleted during acute viremic HIV-1 infection and that ILC numbers did not recover after resolution of peak viremia. ILC numbers were preserved by antiretroviral therapy (ART), but only if initiated during acute infection. Transcriptional profiling during the acute phase revealed upregulation of genes associated with cell death, temporally linked with a strong IFN acute-phase response and evidence of gut barrier breakdown. We found no evidence of tissue redistribution in chronic disease and remaining circulating ILCs were activated but not apoptotic. These data provide a potential mechanistic link between acute HIV-1 infection, lymphoid tissue breakdown, and persistent immune dysfunction.
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http://dx.doi.org/10.1016/j.immuni.2016.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836297PMC
February 2016

Invariant NKT cell development: focus on NOD mice.

Curr Opin Immunol 2014 Apr 13;27:83-8. Epub 2014 Mar 13.

INSERM, U1016, Hospital Cochin/St Vincent de Paul, Paris, France; Université Paris Descartes, Laboratoire d'Excellence INFLAMEX, Sorbonne Paris Cité, Paris, France. Electronic address:

Natural killer T (NKT) cells are non-conventional T lymphocytes expressing a TCRαβ and several NK cell markers. Once activated, they can rapidly secrete large amounts of cytokines such as IFN-γ and IL-4. As a result they can favor both Th1 and Th2 immune responses and play a critical role in anti-pathogenic immune responses as well as in regulation of autoimmune diseases. It has now been clearly established that iNKT cells can be subdivided into three subpopulations: iNKT1, iNKT2 and iNKT17 cells. Each of these populations is characterized by the expression of a particular transcription factor, surface markers and cytokines making them functionally distinct. Interestingly, NOD mice developing autoimmune diabetes exhibit a high frequency of iNKT17 cells, which can participate in the disease.
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http://dx.doi.org/10.1016/j.coi.2014.02.004DOI Listing
April 2014

Plasmacytoid dendritic cells license regulatory T cells, upon iNKT-cell stimulation, to prevent autoimmune diabetes.

Eur J Immunol 2014 May 27;44(5):1454-66. Epub 2014 Feb 27.

INSERM U1016, Institut Cochin, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Laboratoire d'Excellence INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

Invariant NKT (iNKT)-cell stimulation with exogenous specific ligands prevents the development of type 1 diabetes (T1D) in NOD mice. Studies based on anti-islet T-cell transfer showed that iNKT cells prevent the differentiation of these T cells into effector T cells in the pancreatic lymph nodes (PLNs). We hypothesize that this defective priming could be explained by the ability of iNKT cells to induce tolerogenic dendritic cells (DCs) in the PLNs. We evaluated the effect of iNKT-cell stimulation on T1D development by transferring naïve diabetogenic BDC2.5 T cells into proinsulin 2(-/-) NOD mice treated with a long-lasting α-galactosylceramide regimen. In this context, iNKT cells induce the conversion of BDC2.5 T cells into Foxp3(+) Treg cells in the PLNs accumulating in the pancreatic islets. Furthermore, tolerogenic plasmacytoid DCs (pDCs) characterized by low MHC class II molecule expression and TGF-β production are critical in the PLNs for the recruitment of Treg cells into the pancreatic islets by inducing CXCR3 expression. Accordingly, pDC depletion in α-galactosylceramide-treated proinsulin 2(-/-) NOD mice abrogates the protection against T1D. These findings reveal that upon repetitive iNKT-cell stimulation, pDCs are critical for the recruitment of Treg cells in the pancreatic islets and the prevention of T1D development.
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http://dx.doi.org/10.1002/eji.201343910DOI Listing
May 2014

[Regulatory role of NKT cells in the prevention of type 1 diabetes].

Med Sci (Paris) 2013 Aug-Sep;29(8-9):722-8. Epub 2013 Sep 5.

Inserm U1016, Institut Cochin, Paris, France.

Type 1 diabetes is an autoimmune disease resulting from the destruction of pancreatic β cells by the immune system. NKT cells are innate-like T cells that can exert potent immuno-regulatory functions. The regulatory role of NKT cells was initially proposed after the observed decreased frequency of this subset in mouse models of type 1 diabetes, as well as in patients developing various autoimmune pathologies. Increasing NKT cell frequency and function prevent the development of type 1 diabetes in mouse models. Several mechanisms including IL-4 and IL-10 production by NKT cells and the accumulation of tolerogenic dendritic cells are critical for the dampening of pathogenic anti-islet T cell responses by NKT cells. Importantly, these cells can at the same time prevent diabetes and promote efficient immune responses against infectious agents. These results strengthen the potential role of NKT cells as a key target for the development of therapeutic strategies against type 1 diabetes.
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http://dx.doi.org/10.1051/medsci/2013298010DOI Listing
November 2013

Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes.

Nat Med 2013 Jan 16;19(1):65-73. Epub 2012 Dec 16.

Institut National de Santé et de Recherche Médicale (INSERM), U986, Paris, France.

Type 1 diabetes develops over many years and is characterized ultimately by the destruction of insulin-producing pancreatic beta cells by autoreactive T cells. Nonetheless, the role of innate cells in the initiation of this disease remains poorly understood. Here, we show that in young female nonobese diabetic mice, physiological beta cell death induces the recruitment and activation of B-1a cells, neutrophils and plasmacytoid dendritic cells (pDCs) to the pancreas. Activated B-1a cells secrete IgGs specific for double-stranded DNA. IgGs activate neutrophils to release DNA-binding cathelicidin-related antimicrobial peptide (CRAMP), which binds self DNA. Then, self DNA, DNA-specific IgG and CRAMP peptide activate pDCs through the Toll-like receptor 9-myeloid differentiation factor 88 pathway, leading to interferon-α production in pancreatic islets. We further demonstrate through the use of depleting treatments that B-1a cells, neutrophils and IFN-α-producing pDCs are required for the initiation of the diabetogenic T cell response and type 1 diabetes development. These findings reveal that an innate immune cell crosstalk takes place in the pancreas of young NOD mice and leads to the initiation of T1D.
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http://dx.doi.org/10.1038/nm.3042DOI Listing
January 2013

Prevention or acceleration of type 1 diabetes by viruses.

Cell Mol Life Sci 2013 Jan 6;70(2):239-55. Epub 2012 Jul 6.

Université Paris Descartes, [corrected] Hôpital Saint Vincent de Paul/Cochin, Bâtiment [corrected] Petit, 82 Avenue Denfert-Rochereau 75014, Paris, France.

Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells. Even though extensive scientific research has yielded important insights into the immune mechanisms involved in pancreatic β-cell destruction, little is known about the events that trigger the autoimmune process. Recent epidemiological and experimental data suggest that environmental factors are involved in this process. In this review, we discuss the role of viruses as an environmental factor on the development of type 1 diabetes, and the immune mechanisms by which they can trigger or protect against this pathology.
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http://dx.doi.org/10.1007/s00018-012-1042-1DOI Listing
January 2013

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes.

Eur J Immunol 2011 Dec 10;41(12):3574-85. Epub 2011 Nov 10.

INSERM U986, Hôpital Cochin/Saint-Vincent de Paul, Paris, France.

Invariant natural killer T (iNKT) cells are a distinct lineage of innate-like T lymphocytes and converging studies in mouse models have demonstrated the protective role of iNKT cells in the development of type 1 diabetes. Recently, a new subset of iNKT cells, producing high levels of the pro-inflammatory cytokine IL-17, has been identified (iNKT17 cells). Since this cytokine has been implicated in several autoimmune diseases, we have analyzed iNKT17 cell frequency, absolute number and phenotypes in the pancreas and lymphoid organs in non-obese diabetic (NOD) mice. The role of iNKT17 cells in the development of diabetes was investigated using transfer experiments. NOD mice exhibit a higher frequency and absolute number of iNKT17 cells in the lymphoid organs as compared with C57BL/6 mice. iNKT17 cells infiltrate the pancreas of NOD mice where they express IL-17 mRNA. Contrary to the protective role of CD4(+) iNKT cells, the CD4(-) iNKT cell population, which contains iNKT17 cells, enhances the incidence of diabetes. Treatment with a blocking anti-IL-17 antibody prevents the exacerbation of the disease. This study reveals that different iNKT cell subsets play distinct roles in the regulation of type 1 diabetes and iNKT17 cells, which are abundant in NOD mice, exacerbate diabetes development.
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http://dx.doi.org/10.1002/eji.201141751DOI Listing
December 2011

Innate immunity in type 1 diabetes.

Discov Med 2011 Jun;11(61):513-20

Hôpital Saint Vincent de Paul, Paris, France.

Type 1 diabetes (T1D) is a complex autoimmune disease that is untimely caused by the destruction of insulin-producing pancreatic β-cells by autoreactive T cells. The development of the pathology involved several cell types of both the innate and adaptive immune systems. This disease is under the control of several genetic loci of susceptibility but it is also influenced by environmental factors such as infectious agents. Studies in animal models, such as the non-obese diabetic (NOD) mouse, reveal that during the development of T1D multiple interactions occur between macrophages, dendritic cells (DC), natural killer (NK) cells, NKT cells, and lymphocytes. As a consequence, the various components of the immune system can be of peculiar interest as therapeutic targets for disease prevention or cure. This review focuses on the involvement of innate immune cells in the development and the prevention of T1D.
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June 2011