Publications de l'équipe - Lymphocytes CD4+, lymphocytes T innés et cancer - Centre de Recherche Institut Curie
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Publications de l’équipe
Lymphocytes CD4+, lymphocytes T innés et cancer
Année de publication : 2020
Valentin Partula, Mélanie Deschasaux-Tanguy, Stanislas Mondot, Agnès Victor-Bala, Nadia
Bouchemal, Lucie Lecuyer, Christine Bobin-Dubigeon, Marion J Torres, Emmanuelle Kesse-Guyot,
Bruno Charbit, Etienne Patin, Karen E Assmann, Paule Latino-Martel, Chantal Julia, Pilar Galan,
Serge Hercberg, Lluis Quintana-Murci, Matthew L Albert, Darragh Duffy, Olivier Lantz, Philippe
Savarin, Mohamed Nawfal Triba, Mathilde Touvier, (2020 Dec 10)
Associations between untargeted plasma metabolomic signatures and gut
microbiota composition in the population of healthy adults.
The British journal of nutrition : 1-29 : DOI : 10.1017/S0007114520004870
Résumé
Host-microbial co-metabolism products are being increasingly recognized to play important
roles in physiological processes. However, studies undertaking a comprehensive approach to
consider host-microbial metabolic relationships remain scarce. Metabolomic analysis yielding
detailed information regarding metabolites found in a given biological compartment holds
promise for such an approach. This work aimed to explore the associations between host
plasma metabolomic signatures and gut microbiota composition in healthy adults of the
Milieu Intérieur study. For 846 subjects, gut microbiota composition was profiled through
sequencing of the 16S rRNA gene in stools. Metabolomic signatures were generated through
proton nuclear magnetic resonance analysis of plasma. The associations between
metabolomic variables and α- and β-diversity indexes and relative taxa abundances were
tested using multi-adjusted partial Spearman correlations, PERMANOVAs, and MaAsLins,
respectively. A Multiple testing correction was applied (Benjamini-Hochberg, 10%-FDR).
Microbial richness was negatively associated with lipid-related signals and positively
associated with amino acids, choline, creatinine, glucose, and citrate (-0.133 ≤ Spearman’s ρ
≤ 0.126). Specific associations between metabolomic signals and abundances of taxa were
detected (25 at the genus level and 19 at the species level): notably, numerous associations
were observed for creatinine (positively associated with 11 species, and negatively
associated with Faecalibacterium prausnitzii). This large-scale population-based study
highlights metabolites associated with gut microbial features and provides new insights into
the understanding of complex host-gut microbiota metabolic relationships. In particular, our
results support the implication of a « gut-kidney axis ». More studies providing a detailed
exploration of these complex interactions, and their implications for host health are needed.
Silvia Menegatti, Vincent Guillemot, Eleonora Latis, Hanane Yahia-Cherbal, Daniela Mittermüller,
Vincent Rouilly, Elena Mascia, Nicolas Rosine, Surya Koturan, Gael A Millot, Claire Leloup,
Darragh Duffy, Aude Gleizes, Salima Hacein-Bey-Abina, , Jérémie Sellam, Francis Berenbaum,
Corinne Miceli, Maxime Dougados, Elisabetta Bianchi, Lars Rogge (2020 Dec 3)
Immune response profiling of patients with spondyloarthritis reveals signalling
networks mediating TNF-blocker function in vivo.
Annals of the rheumatic diseases : DOI : annrheumdis-2020-218304
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1Publications de l’équipe
Lymphocytes CD4+, lymphocytes T innés et cancer
Résumé
Antitumour necrosis factor (TNF) therapy has revolutionised treatment of several chronic
inflammatory diseases, including spondyloarthritis (SpA). However, TNF inhibitors (TNFi) are
not effective in all patients and the biological basis for treatment failure remains unknown.
We have analysed induced immune responses to define the mechanism of action of TNF
blockers in SpA and to identify immunological correlates of responsiveness to TNFi.
François Anna, Sophie Goyard, Ana Ines Lalanne, Fabien Nevo, Marion Gransagne, Philippe
Souque, Delphine Louis, Véronique Gillon, Isabelle Turbiez, François-Clément Bidard, Aline
Gobillion, Alexia Savignoni, Maude Guillot-Delost, François Dejardin, Evelyne Dufour, Stéphane
Petres, Odile Richard-Le Goff, Zaineb Choucha, Olivier Helynck, Yves L Janin, Nicolas Escriou,
Pierre Charneau, Franck Perez, Thierry Rose, Olivier Lantz (2020 Dec 1)
High seroprevalence but short-lived immune response to SARS-CoV-2 infection
in Paris.
European journal of immunology : DOI : 10.1002/eji.202049058
Résumé
Although the COVID-19 pandemic peaked in March/April 2020 in France, the prevalence of
infection is barely known. Using high-throughput methods, we assessed herein the
serological response against the SARS-CoV-2 virus of 1847 participants working in three sites
of an institution in Paris conurbation. In May-July 2020, 11% (95% CI: 9.7-12.6) of serums
were positive for IgG against the SARS-CoV-2 N and S proteins, and 9.5% (CI:8.2-11.0) were
neutralizer in pseudo-typed virus assays. The prevalence of seroconversion was 11.6%
(CI:10.2-13.2) when considering positivity in at least one assays. In 5% of RT-qPCR positive
individuals, no systemic IgGs were detected. Among immune individuals, 21% had been
asymptomatic. Anosmia (loss of smell) and ageusia (loss of taste) occurred in 52% of the
IgG-positive individuals and in 3% of the negative ones. In contrast, 30% of the anosmia-
ageusia cases were seronegative suggesting that the true prevalence of infection may have
reached 16.6%. In sera obtained 4-8 weeks after the first sampling anti-N and anti-S IgG
titers and neutralization activity in pseudo-virus assay declined by 31%, 17% and 53%,
resulting thus in half-life of respectively 35, 87 and 28 days. The population studied is
representative of active workers in Paris. The short lifespan of the serological systemic
responses suggests an underestimation of the true prevalence of infection. This article is
protected by copyright. All rights reserved.
François Legoux, Marion Salou, Olivier Lantz (2020 Oct 14)
MAIT Cell Development and Functions: the Microbial Connection.
Immunity : 710-723 : DOI : S1074-7613(20)30403-9
Résumé
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2Publications de l’équipe
Lymphocytes CD4+, lymphocytes T innés et cancer
Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved T cell subset,
which reacts to most bacteria through T cell receptor (TCR)-mediated recognition of
metabolites derived from the vitamin B2 biosynthetic pathway. Microbiota-derived signals
affect all stages of MAIT cell biology including intra-thymic development, peripheral
expansion, and functions in specific organs. In tissues, MAIT cells can integrate multiple
signals and display effector functions involved in the defense against infectious pathogens.
In addition to anti-bacterial activity, MAIT cells improve wound healing in the skin, suggesting
a role in epithelium homeostasis through bi-directional interactions with the local microbiota.
In humans, blood MAIT cell frequency is modified during several auto-immune diseases,
which are often associated with microbiota dysbiosis, further emphasizing the potential
interplay of MAIT cells with the microbiota. Here, we will review how microbes interact with
MAIT cells, from initial intra-thymic development to tissue colonization and functions.
Amine Toubal, Badr Kiaf, Lucie Beaudoin, Lucie Cagninacci, Moez Rhimi, Blandine Fruchet,
Jennifer da Silva, Alexandra J Corbett, Yannick Simoni, Olivier Lantz, Jamie Rossjohn, James
McCluskey, Philippe Lesnik, Emmanuelle Maguin, Agnès Lehuen (2020 Jul 26)
Mucosal-associated invariant T cells promote inflammation and intestinal
dysbiosis leading to metabolic dysfunction during obesity.
Nature communications : 3755 : DOI : 10.1038/s41467-020-17307-0
Résumé
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.
Nicolas Gonzalo Núñez, Jimena Tosello Boari, Rodrigo Nalio Ramos, Wilfrid Richer, Nicolas
Cagnard, Cyrill Dimitri Anderfuhren, Leticia Laura Niborski, Jeremy Bigot, Didier Meseure,
Philippe De La Rochere, Maud Milder, Sophie Viel, Delphine Loirat, Louis Pérol, Anne Vincent-
Salomon, Xavier Sastre-Garau, Becher Burkhard, Christine Sedlik, Olivier Lantz, Sebastian
Amigorena, Eliane Piaggio (2020 Jul 1)
Tumor invasion in draining lymph nodes is associated with Treg accumulation in
breast cancer patients.
Nature communications : 3272 : DOI : 10.1038/s41467-020-17046-2
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 3Publications de l’équipe
Lymphocytes CD4+, lymphocytes T innés et cancer
Résumé
Tumor-draining lymph node (TDLN) invasion by metastatic cells in breast cancer correlates
with poor prognosis and is associated with local immunosuppression, which can be partly
mediated by regulatory T cells (Tregs). Here, we study Tregs from matched tumor-invaded
and non-invaded TDLNs, and breast tumors. We observe that Treg frequencies increase with
nodal invasion, and that Tregs express higher levels of co-inhibitory/stimulatory receptors
than effector cells. Also, while Tregs show conserved suppressive function in TDLN and
tumor, conventional T cells (Tconvs) in TDLNs proliferate and produce Th1-inflammatory
cytokines, but are dysfunctional in the tumor. We describe a common transcriptomic
signature shared by Tregs from tumors and nodes, including CD80, which is significantly
associated with poor patient survival. TCR RNA-sequencing analysis indicates trafficking
between TDLNs and tumors and ongoing Tconv/Treg conversion. Overall, TDLN Tregs are
functional and express a distinct pattern of druggable co-receptors, highlighting their
potential as targets for cancer immunotherapy.
Geoffrey M Lynn, Christine Sedlik, Faezzah Baharom, Yaling Zhu, Ramiro A Ramirez-Valdez,
Vincent L Coble, Kennedy Tobin, Sarah R Nichols, Yaakov Itzkowitz, Neeha Zaidi, Joshua M
Gammon, Nicolas J Blobel, Jordan Denizeau, Philippe de la Rochere, Brian J Francica, Brennan
Decker, Mateusz Maciejewski, Justin Cheung, Hidehiro Yamane, Margery G Smelkinson, Joseph R
Francica, Richard Laga, Joshua D Bernstock, Leonard W Seymour, Charles G Drake, Christopher
M Jewell, Olivier Lantz, Eliane Piaggio, Andrew S Ishizuka, Robert A Seder (2020 Jan 15)
Peptide-TLR-7/8a conjugate vaccines chemically programmed for nanoparticle
self-assembly enhance CD8 T-cell immunity to tumor antigens.
Nature biotechnology : 320-332 : DOI : 10.1038/s41587-019-0390-x
Résumé
Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer
treatment modality; however, neoantigen physicochemical variability can present challenges
to manufacturing personalized cancer vaccines in an optimal format for inducing anticancer
T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified
peptide-TLR-7/8a conjugates that are chemically programmed to self-assemble into
nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This
approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a
(adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting
cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted
neoantigens (n = 179) from three tumor models induced CD8 T cells against ~50% of
neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance.
SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in
nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering
peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity.
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 4Publications de l’équipe
Lymphocytes CD4+, lymphocytes T innés et cancer
Année de publication : 2019
Marion Salou, Olivier Lantz (2019 Oct 19)
A TCR-Dependent Tissue Repair Potential of MAIT Cells.
Trends in immunology : DOI : S1471-4906(19)30189-9
Résumé
Three studies published in Cell Reports (Hinks et al., Lamichhane et al., and Leng et al.)
describe the transcriptome of human and mouse mucosal-associated invariant T (MAIT) cells
after cognate and noncognate stimulation. The results confirm the variability of MAIT cell
effector functions and provide evidence of a new tissue-repair gene signature expressed
upon T cell receptor (TCR) stimulation.
Petar Scepanovic, Flavia Hodel, Stanislas Mondot, Valentin Partula, Allyson Byrd, Christian
Hammer, Cécile Alanio, Jacob Bergstedt, Etienne Patin, Mathilde Touvier, Olivier Lantz, Matthew
L Albert, Darragh Duffy, Lluis Quintana-Murci, Jacques Fellay, (2019 Sep 15)
A comprehensive assessment of demographic, environmental, and host genetic
associations with gut microbiome diversity in healthy individuals.
Microbiome : 130 : DOI : 10.1186/s40168-019-0747-x
Résumé
The gut microbiome is an important determinant of human health. Its composition has been
shown to be influenced by multiple environmental factors and likely by host genetic
variation. In the framework of the Milieu Intérieur Consortium, a total of 1000 healthy
individuals of western European ancestry, with a 1:1 sex ratio and evenly stratified across
five decades of life (age 20-69), were recruited. We generated 16S ribosomal RNA profiles
from stool samples for 858 participants. We investigated genetic and non-genetic factors
that contribute to individual differences in fecal microbiome composition.
Scepanovic P, Hodel F, Mondot S, Partula V, Byrd A, Hammer C, Alanio C, Bergstedt J, Patin E,
Touvier M, Lantz O, Albert ML, Duffy D, Quintana-Murci L, Fellay J; Milieu Intérieur Consortium.
(2019 Sep 13)
xA comprehensive assessment of demographic, environmental, and host genetic
associations with gut microbiome diversity in healthy individuals.
: 13;7(1) : 130 : DOI : 10.1186/s40168-019-0747-x
Résumé
François Legoux, Déborah Bellet, Celine Daviaud, Yara El Morr, Aurelie Darbois, Kristina Niort,
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 5Publications de l’équipe
Lymphocytes CD4+, lymphocytes T innés et cancer
Emanuele Procopio, Marion Salou, Jules Gilet, Bernhard Ryffel, Aurélie Balvay, Anne Foussier,
Manal Sarkis, Ahmed El Marjou, Frederic Schmidt, Sylvie Rabot, Olivier Lantz (2019 Aug 31)
Microbial metabolites control the thymic development of mucosal-associated
invariant T cells.
Science (New York, N.Y.) : DOI : eaaw2719
Résumé
How the microbiota modulate immune functions remains poorly understood. Mucosal-
associated invariant T (MAIT) cells are implicated in mucosal homeostasis and absent in
germ-free mice. Here, we show that commensal bacteria govern murine MAIT intrathymic
development, as MAIT cells did not recirculate to the thymus. MAIT development required
expression in bacteria, indicating that production of the MAIT antigen 5-(2-
oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) was necessary. 5-OP-RU rapidly
traveled from mucosal surfaces to the thymus, where it was captured by the major
histocompatibility complex class Ib molecule MR1. This led to increased numbers of the
earliest MAIT precursors and the expansion of more mature receptor-related orphan receptor
γt-positive MAIT cells. Thus, a microbiota-derived metabolite controls development of
mucosally targeted T cells, in a process blurring the distinction between exogenous and self-
antigens.
François Legoux, Jules Gilet, Emanuele Procopio, Klara Echasserieau, Karine Bernardeau, Olivier
Lantz (2019 Aug 22)
Molecular mechanisms of lineage decisions in metabolite-specific T cells.
Nature immunology : 1244-1255 : DOI : 10.1038/s41590-019-0465-3
Résumé
Mucosal-associated invariant T cells (MAIT cells) recognize the microbial metabolite 5-(2-
oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) presented by the MHC class Ib
molecule, MR1. MAIT cells acquire effector functions during thymic development, but the
mechanisms involved are unclear. Here we used single-cell RNA-sequencing to characterize
the developmental path of 5-OP-RU-specific thymocytes. In addition to the known MAIT1 and
MAIT17 effector subsets selected on bone-marrow-derived hematopoietic cells, we identified
5-OP-RU-specific thymocytes that were selected on thymic epithelial cells and differentiated
into CD44 naive T cells. MAIT cell positive selection required signaling through the adapter,
SAP, that controlled the expression of the transcription factor, ZBTB16. Pseudotemporal
ordering of single cells revealed transcriptional trajectories of 5-OP-RU-specific thymocytes
selected on either thymic epithelial cells or hematopoietic cells. The resulting model
illustrates T cell lineage decisions.
Olivier Lantz, François Legoux (2019 May 30)
MAIT cells: programmed in the thymus to mediate immunity within tissues.
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 6Publications de l’équipe
Lymphocytes CD4+, lymphocytes T innés et cancer
Current opinion in immunology : 75-82 : DOI : S0952-7915(18)30079-7
Résumé
MAIT cells are an evolutionarily conserved T cell subset recognizing ubiquitous microbial
metabolites. Herein, we review recent literature showing that MAIT cells can be divided into
type 1 and type 17 subsets, which acquire a tissue resident differentiation program in the
thymus and localize in specific tissues. We also discuss the nature and in vivo availability of
the different agonist and antagonist MAIT ligands with potential consequences for MAIT cell
biology.
Salou M1, Legoux F1, Gilet J1, Darbois A1, du Halgouet A1, Alonso R1, Richer W1, Goubet AG1,
Daviaud C2, Menger L1, Procopio E1, Premel V1, Lantz O3,4,5. (2019 Jan 27)
A common transcriptomic program acquired in the thymus defines tissue
residency of MAIT and NKT subsets.
Journal of experimental medecine : 216 : J Exp Med. 2019 Jan 7;216(1):133-151. doi:
10.1084/jem.20181483. Epub 2018 Dec 5. : 133,151 : DOI : 10.1084/jem.20181483
Résumé
Mucosal-associated invariant T (MAIT) cells are abundant T cells with unique specificity for
microbial metabolites. MAIT conservation along evolution indicates important functions, but
their low frequency in mice has hampered their detailed characterization. Here, we
performed the first transcriptomic analysis of murine MAIT cells. MAIT1 (RORγtneg) and
MAIT17 (RORγt+) subsets were markedly distinct from mainstream T cells, but quasi-identical
to NKT1 and NKT17 subsets. The expression of similar programs was further supported by
strong correlations of MAIT and NKT frequencies in various organs. In both mice and humans,
MAIT subsets expressed gene signatures associated with tissue residency. Accordingly,
parabiosis experiments demonstrated that MAIT and NKT cells are resident in the spleen,
liver, and lungs, with LFA1/ICAM1 interactions controlling MAIT1 and NKT1 retention in spleen
and liver. The transcriptional program associated with tissue residency was already
expressed in thymus, as confirmed by adoptive transfer experiments. Altogether, shared
thymic differentiation processes generate « preset » NKT and MAIT subsets with defined
effector functions, associated with specific positioning into tissues.
Année de publication : 2018
Marion Salou, François Legoux, Jules Gilet, Aurélie Darbois, Anastasia du Halgouet, Ruby Alonso,
Wilfrid Richer, Anne-Gaëlle Goubet, Céline Daviaud, Laurie Menger, Emanuele Procopio, Virginie
Premel, Olivier Lantz (2018 Dec 7)
A common transcriptomic program acquired in the thymus defines tissue
residency of MAIT and NKT subsets.
The Journal of experimental medicine : 133-151 : DOI : 10.1084/jem.20181483
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 7Publications de l’équipe
Lymphocytes CD4+, lymphocytes T innés et cancer
Résumé
Mucosal-associated invariant T (MAIT) cells are abundant T cells with unique specificity for
microbial metabolites. MAIT conservation along evolution indicates important functions, but
their low frequency in mice has hampered their detailed characterization. Here, we
performed the first transcriptomic analysis of murine MAIT cells. MAIT1 (RORγt) and MAIT17
(RORγt) subsets were markedly distinct from mainstream T cells, but quasi-identical to NKT1
and NKT17 subsets. The expression of similar programs was further supported by strong
correlations of MAIT and NKT frequencies in various organs. In both mice and humans, MAIT
subsets expressed gene signatures associated with tissue residency. Accordingly, parabiosis
experiments demonstrated that MAIT and NKT cells are resident in the spleen, liver, and
lungs, with LFA1/ICAM1 interactions controlling MAIT1 and NKT1 retention in spleen and liver.
The transcriptional program associated with tissue residency was already expressed in
thymus, as confirmed by adoptive transfer experiments. Altogether, shared thymic
differentiation processes generate « preset » NKT and MAIT subsets with defined effector
functions, associated with specific positioning into tissues.
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 8You can also read
