@article{pmid39794349,

title = {Heterochromatic gene silencing controls CD4 T cell susceptibility to regulatory T cell-mediated suppression in a murine allograft model},

author = {Julie Noguerol and Karl Laviolette and Margot Zahm and Adeline Chaubet and Ambrine Sahal and Claire Détraves and Romain Torres and Clothilde Demont and Véronique Adoue and Carine Joffre and Florence Cammas and Joost Pm van Meerwijk and Olivier P Joffre},

doi = {10.1038/s41467-025-55848-4},

issn = {2041-1723},

year  = {2025},

date = {2025-01-01},

urldate = {2025-01-01},

journal = {Nat Commun},

volume = {16},

number = {1},

pages = {566},

abstract = {Protective immune responses require close interactions between conventional (Tconv) and regulatory T cells (Treg). The extracellular mediators and signaling events that regulate the crosstalk between these CD4 T cell subsets have been extensively characterized. However, how Tconv translate Treg-dependent suppressive signals at the chromatin level remains largely unknown. Here we show, using a murine bone marrow allograft model in which graft rejection is coordinated by CD4 T cells and can be inhibited by Treg, that Treg-mediated T cell suppression involves Heterochromatin Protein 1 α (HP1α)-dependent gene silencing. Unexpectedly, our screen also reveals that T cells deficient for HP1γ or the methyltransferase SUV39H1 are better repressed by Treg than their wild-type counterparts. Mechanistically, our transcriptional and epigenetic profiling identifies HP1γ as a negative regulator of a gene network functionally associated with T-cell exhaustion, including those encoding the inhibitory receptors PD-1 and LAG-3. In conclusion, we identify HP1 variants as rheostats that finely tune the balance between tolerance and immunity. While HP1α converts immunosuppressive signals into heterochromatin-dependent gene silencing mechanisms, HP1γ adjusts Tconv sensitivity to inhibitory environmental signals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39231385,

title = {Impact of the Multiple Sclerosis-Associated Genetic Variant  Gly307Ser on Human CD8 T-Cell Functions},

author = {Elena Morandi and Véronique Adoue and Isabelle Bernard and Ekaterina Friebel and Nicolas Nunez and Yann Aubert and Frederick Masson and Anne S Dejean and Burkhard Becher and Anne Astier and Ludovic Martinet and Abdelhadi Saoudi},

doi = {10.1212/NXI.0000000000200306},

issn = {2332-7812},

year  = {2024},

date = {2024-11-01},

urldate = {2024-11-01},

journal = {Neurol Neuroimmunol Neuroinflamm},

volume = {11},

number = {6},

pages = {e200306},

abstract = {BACKGROUND AND OBJECTIVES: The rs763361 nonsynonymous variant in the  gene, which results in a glycine-to-serine substitution at position 307 of the CD226 protein, has been implicated as a risk factor of various immune-mediated diseases, including multiple sclerosis (MS). Compelling evidence suggests that this allele may play a significant role in predisposing individuals to MS by decreasing the immune-regulatory capacity of Treg cells and increasing the proinflammatory potential of effector CD4 T cells. However, the impact of this CD226 gene variant on CD8 T-cell functions, a population that also plays a key role in MS, remains to be determined.nnMETHODS: To study whether the CD226 risk variant affects human CD8 T-cell functions, we used CD8 T cells isolated from peripheral blood mononuclear cell of 16 age-matched healthy donors homozygous for either the protective or the risk allele of CD226. We characterized these CD8 T cells on T-cell receptor (TCR) stimulation using high-parametric flow cytometry and bulk RNAseq and through characterization of canonical signaling pathways and cytokine production.nnRESULTS: On TCR engagement, the phenotype of ex vivo CD8 T cells bearing the protective (CD226-307Gly) or the risk (CD226-307Ser) allele of CD226 was largely overlapping. However, the transcriptomic signature of CD8 T cells from the donors carrying the risk allele presented an enrichment in TCR, JAK/STAT, and IFNγ signaling. We next found that the CD226-307Ser risk allele leads to a selective increase in the phosphorylation of the mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 (ERK1/2) associated with enhanced phosphorylation of STAT4 and increased production of IFNγ.nnDISCUSSION: Our data suggest that the CD226-307Ser risk variant imposes immune dysregulation by increasing the pathways related to IFNγ signaling in CD8 T cells, thereby contributing to the risk of developing chronic inflammation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38834865,

title = {Cell shape sensing licenses dendritic cells for homeostatic migration to lymph nodes},

author = {Zahraa Alraies and Claudia A Rivera and Maria-Graciela Delgado and Doriane Sanséau and Mathieu Maurin and Roberto Amadio and Giulia Maria Piperno and Garett Dunsmore and Aline Yatim and Livia Lacerda Mariano and Anna Kniazeva and Vincent Calmettes and Pablo J Sáez and Alice Williart and Henri Popard and Matthieu Gratia and Olivier Lamiable and Aurélie Moreau and Zoé Fusilier and Lou Crestey and Benoit Albaud and Patricia Legoix and Anne S Dejean and Anne-Louise Le Dorze and Hideki Nakano and Donald N Cook and Toby Lawrence and Nicolas Manel and Federica Benvenuti and Florent Ginhoux and Hélène D Moreau and Guilherme P F Nader and Matthieu Piel and Ana-Maria Lennon-Duménil},

doi = {10.1038/s41590-024-01856-3},

issn = {1529-2916},

year  = {2024},

date = {2024-07-01},

urldate = {2024-07-01},

journal = {Nat Immunol},

volume = {25},

number = {7},

pages = {1193--1206},

abstract = {Immune cells experience large cell shape changes during environmental patrolling because of the physical constraints that they encounter while migrating through tissues. These cells can adapt to such deformation events using dedicated shape-sensing pathways. However, how shape sensing affects immune cell function is mostly unknown. Here, we identify a shape-sensing mechanism that increases the expression of the chemokine receptor CCR7 and guides dendritic cell migration from peripheral tissues to lymph nodes at steady state. This mechanism relies on the lipid metabolism enzyme cPLA, requires nuclear envelope tensioning and is finely tuned by the ARP2/3 actin nucleation complex. We also show that this shape-sensing axis reprograms dendritic cell transcription by activating an IKKβ-NF-κB-dependent pathway known to control their tolerogenic potential. These results indicate that cell shape changes experienced by immune cells can define their migratory behavior and immunoregulatory properties and reveal a contribution of the physical properties of tissues to adaptive immunity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38565808,

title = {Positive regulation of Vav1 by Themis controls CD4 T cell pathogenicity in a mouse model of central nervous system inflammation},

author = {Remi Marrocco and Isabelle Bernard and Emeline Joulia and Rebecca Barascud and Anne S Dejean and Renaud Lesourne and Abdelhadi Saoudi},

doi = {10.1007/s00018-024-05203-5},

issn = {1420-9071},

year  = {2024},

date = {2024-04-01},

urldate = {2024-04-01},

journal = {Cell Mol Life Sci},

volume = {81},

number = {1},

pages = {161},

abstract = {The susceptibility to autoimmune diseases is conditioned by the association of modest genetic alterations which altogether weaken self-tolerance. The mechanism whereby these genetic interactions modulate T-cell pathogenicity remains largely uncovered. Here, we investigated the epistatic interaction of two interacting proteins involved in T Cell Receptor signaling and which were previously associated with the development of Multiple Sclerosis. To this aim, we used mice expressing an hypomorphic variant of Vav1 (Vav1), combined with a T cell-conditional deletion of Themis. We show that the combined mutations in Vav1 and Themis induce a strong attenuation of the severity of Experimental Autoimmune Encephalomyelitis (EAE), contrasting with the moderate effect of the single mutation in each of those two proteins. This genotype-dependent gradual decrease of EAE severity correlates with decreased quantity of phosphorylated Vav1 in CD4 T cells, establishing that Themis promotes the development of encephalitogenic Tconv response by enhancing Vav1 activity. We also show that the cooperative effect of Themis and Vav1 on EAE severity is independent of regulatory T cells and unrelated to the impact of Themis on thymic selection. Rather, it results from decreased production of pro-inflammatory cytokines (IFN-γ, IL-17, TNF and GM-CSF) and reduced T cell infiltration in the CNS. Together, our results provide a rationale to study combination of related genes, in addition to single gene association, to better understand the genetic bases of human diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38189779,

title = {Eomes-dependent mitochondrial regulation promotes survival of pathogenic CD4+ T cells during inflammation},

author = {Emeline Joulia and Michaël F Michieletto and Arantxa Agesta and Cindy Peillex and Virginie Girault and Anne-Louise Le Dorze and Romain Peroceschi and Florence Bucciarelli and Marion Szelechowski and Adeline Chaubet and Nawad Hakim and Rémi Marrocco and Emeline Lhuillier and Manuel Lebeurrier and Rafael J Argüello and Abdelhadi Saoudi and Hicham El Costa and Veronique Adoue and Thierry Walzer and Jean-Emmanuel Sarry and Anne S Dejean},

doi = {10.1084/jem.20230449},

issn = {1540-9538},

year  = {2024},

date = {2024-02-01},

urldate = {2024-02-01},

journal = {J Exp Med},

volume = {221},

number = {2},

abstract = {The mechanisms whereby Eomes controls tissue accumulation of T cells and strengthens inflammation remain ill-defined. Here, we show that Eomes deletion in antigen-specific CD4+ T cells is sufficient to protect against central nervous system (CNS) inflammation. While Eomes is dispensable for the initial priming of CD4+ T cells, it is required for long-term maintenance of CNS-infiltrating CD4+ T cells. We reveal that the impact of Eomes on effector CD4+ T cell longevity is associated with sustained expression of multiple genes involved in mitochondrial organization and functions. Accordingly, epigenetic studies demonstrate that Eomes supports mitochondrial function by direct binding to either metabolism-associated genes or mitochondrial transcriptional modulators. Besides, the significance of these findings was confirmed in CD4+ T cells from healthy donors and multiple sclerosis patients. Together, our data reveal a new mechanism by which Eomes promotes severity and chronicity of inflammation via the enhancement of CD4+ T cell mitochondrial functions and resistance to stress-induced cell death.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37012202,

title = {C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress-Induced Ferroptosis in FLT3-Mutant Leukemia},

author = {Marie Sabatier and Rudy Birsen and Laura Lauture and Sarah Mouche and Paolo Angelino and Jonas Dehairs and Léa Goupille and Ismael Boussaid and Maël Heiblig and Emeline Boet and Ambrine Sahal and Estelle Saland and Juliana C Santos and Marc Armengol and Miranda Fernández-Serrano and Thomas Farge and Guillaume Cognet and Federico Simonetta and Corentin Pignon and Antoine Graffeuil and Céline Mazzotti and Hervé Avet-Loiseau and Océane Delos and Justine Bertrand-Michel and Amélie Chedru and Vilma Dembitz and Paolo Gallipoli and Natasha S Anstee and Sun Loo and Andrew H Wei and Martin Carroll and Armelle Goubard and Rémy Castellano and Yves Collette and François Vergez and Véronique Mansat-De Mas and Sarah Bertoli and Suzanne Tavitian and Muriel Picard and Christian Récher and Nathalie Bourges-Abella and Fanny Granat and Olivier Kosmider and Pierre Sujobert and Benoit Colsch and Carine Joffre and Lucille Stuani and Johannes V Swinnen and Hervé Guillou and Gael Roué and Nawad Hakim and Anne S Dejean and Petros Tsantoulis and Clément Larrue and Didier Bouscary and Jerome Tamburini and Jean-Emmanuel Sarry},

doi = {10.1158/2159-8290.CD-22-0411},

issn = {2159-8290},

year  = {2023},

date = {2023-07-01},

urldate = {2023-07-01},

journal = {Cancer Discov},

volume = {13},

number = {7},

pages = {1720--1747},

abstract = {Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)-stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application.nnSIGNIFICANCE: FLT3 mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. This article is highlighted in the In This Issue feature, p. 1501.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35857631,

title = {THEMIS enhances the magnitude of normal and neuroinflammatory type 1 immune responses by promoting TCR-independent signals},

author = {Cui Yang and Gaëtan Blaize and Rémi Marrocco and Nelly Rouquié and Cyrielle Bories and Mylène Gador and Suzanne Mélique and Emeline Joulia and Mehdi Benamar and Anne S Dejean and Hélène Daniels-Treffandier and Paul E Love and Nicolas Fazilleau and Abdelhadi Saoudi and Renaud Lesourne},

doi = {10.1126/scisignal.abl5343},

issn = {1937-9145},

year  = {2022},

date = {2022-07-01},

urldate = {2022-07-01},

journal = {Sci Signal},

volume = {15},

number = {742},

pages = {eabl5343},

abstract = {Signals that determine the differentiation of naïve CD4 T helper (T) cells into specific effector cell subsets are primarily stimulated by cytokines, but additional signals are required to adjust the magnitude of T cell responses and set the balance between effective immunity and immunological tolerance. By inducing the post-thymic deletion of the T cell lineage signaling protein THEMIS, we showed that THEMIS promoted the development of optimal type 1 immune responses to foreign antigens but stimulated signals that favored encephalitogenic responses to self-neuroantigens. THEMIS was required to stimulate the expression of the gene encoding the transcriptional regulator T-BET and the production of the cytokine interferon-γ (IFN-γ), and it enhanced the ability of encephalitogenic CD4 T cells to migrate into the central nervous system. Consistently, analysis of THEMIS expression in polarized CD4 T cells showed that THEMIS was selectively increased in abundance in T1 cells. The stimulation of predifferentiated effector CD4 T cells with antigen-presenting cells revealed a stimulatory function for THEMIS on type 1 cytokine responses, similar to those observed ex vivo after immunization. In contrast, THEMIS exerted opposing effects on naïve CD4 T cells in vitro by inhibiting the T cell receptor (TCR)-mediated signals that lead to T1 cell responses. These data suggest that THEMIS exerts TCR-independent functions in effector T cells, which increase the magnitude of normal and pathogenic T1 cell-mediated responses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36483552,

title = {The mechanisms underlying the immune control of Zika virus infection at the maternal-fetal interface},

author = {Ana Espino and Jordi Gouilly and Qian Chen and Philippe Colin and Paul Guerby and Jacques Izopet and Ali Amara and Julie Tabiasco and Reem Al-Daccak and Hicham El Costa and Nabila Jabrane-Ferrat},

doi = {10.3389/fimmu.2022.1000861},

issn = {1664-3224},

year  = {2022},

date = {2022-01-01},

urldate = {2022-01-01},

journal = {Front Immunol},

volume = {13},

pages = {1000861},

abstract = {Unlike other Flaviviruses, Zika virus (ZIKV) infection during the first trimester of pregnancy causes severe pregnancy outcomes including the devastating microcephaly and diseases associated with placental dysfunctions. We have previously reported that the maternal decidua basalis, the major maternal-fetal interface, serves as a replication platform enabling virus amplification before dissemination to the fetal compartment. However, the rate of congenital infection is quite low, suggesting the presence of a natural barrier against viral infection. Using primary cells from first-trimester pregnancy samples, we investigated in this study how the maternal decidua can interfere with ZIKV infection. Our study reveals that whether through their interactions with dNK cells, the main immune cell population of the first-trimester decidua, or their production of proinflammatory cytokines, decidual stromal cells (DSCs) are the main regulators of ZIKV infection during pregnancy. We also validate the functional role of AXL as a crucial receptor for ZIKV entry in DSCs and demonstrate that targeted inhibition of ligand-receptor interaction at the early stage of the infection is effective in drastically reducing virus pathogenesis at the maternal-fetal interface. Collectively, our results provide insights into the mechanisms through which ZIKV infection and spreading can be limited. The strategy of circumventing viral entry at the maternal-fetus interface limits virus dissemination to fetal tissues, thereby preventing congenital abnormalities.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34985667,

title = {Decidua Basalis: An Ex Vivo Model to Study HIV-1 Infection During Pregnancy and Beyond},

author = {Nabila Jabrane-Ferrat and Hicham El Costa},

doi = {10.1007/978-1-0716-1871-4_15},

issn = {1940-6029},

year  = {2022},

date = {2022-01-01},

urldate = {2022-01-01},

journal = {Methods Mol Biol},

volume = {2407},

pages = {205--213},

abstract = {The human decidua basalis, main uterine mucosa during pregnancy, provides an ex vivo model for studying natural protection of macrophages against HIV-1 infection at the mucosal level. Beyond pregnancy, the decidua constitutes also a valuable tool to assess tissue-resident macrophage infection. Here, we provide a detailed protocol for decidual macrophage purification and tissue infection.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34521844,

title = {Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells},

author = {Jiang Zhang and Stéphanie Le Gras and Kevin Pouxvielh and Fabrice Faure and Lucie Fallone and Nicolas Kern and Marion Moreews and Anne-Laure Mathieu and Raphaël Schneider and Quentin Marliac and Mathieu Jung and Aurore Berton and Simon Hayek and Pierre-Olivier Vidalain and Antoine Marçais and Garvin Dodard and Anne Dejean and Laurent Brossay and Yad Ghavi-Helm and Thierry Walzer},

doi = {10.1038/s41467-021-25758-2},

issn = {2041-1723},

year  = {2021},

date = {2021-09-01},

urldate = {2021-09-01},

journal = {Nat Commun},

volume = {12},

number = {1},

pages = {5446},

abstract = {EOMES and T-BET are related T-box transcription factors that control natural killer (NK) cell development. Here we demonstrate that EOMES and T-BET regulate largely distinct gene sets during this process. EOMES is dominantly expressed in immature NK cells and drives early lineage specification by inducing hallmark receptors and functions. By contrast, T-BET is dominant in mature NK cells, where it induces responsiveness to IL-12 and represses the cell cycle, likely through transcriptional repressors. Regardless, many genes with distinct functions are co-regulated by the two transcription factors. By generating two gene-modified mice facilitating chromatin immunoprecipitation of endogenous EOMES and T-BET, we show a strong overlap in their DNA binding targets, as well as extensive epigenetic changes during NK cell differentiation. Our data thus suggest that EOMES and T-BET may distinctly govern, via differential expression and co-factors recruitment, NK cell maturation by inserting partially overlapping epigenetic regulations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33617602,

title = {Effector memory CD8 T cell response elicits Hepatitis E Virus genotype 3 pathogenesis in the elderly},

author = {Hicham El Costa and Jordi Gouilly and Florence Abravanel and Elmostafa Bahraoui and Jean-Marie Peron and Nassim Kamar and Nabila Jabrane-Ferrat and Jacques Izopet},

doi = {10.1371/journal.ppat.1009367},

issn = {1553-7374},

year  = {2021},

date = {2021-02-01},

urldate = {2021-02-01},

journal = {PLoS Pathog},

volume = {17},

number = {2},

pages = {e1009367},

abstract = {Genotype 3 Hepatitis E virus (HEV-3) is an emerging threat for aging population. More than one third of older infected patients develops clinical symptoms with severe liver damage, while others remain asymptomatic. The origin of this discrepancy is still elusive although HEV-3 pathogenesis appears to be immune-mediated. Therefore, we investigated the role of CD8 T cells in the outcome of the infection in immunocompetent elderly subjects. We enrolled twenty two HEV-3-infected patients displaying similar viral determinants and fifteen healthy donors. Among the infected group, sixteen patients experienced clinical symptoms related to liver disease while six remained asymptomatic. Here we report that symptomatic infection is characterized by an expansion of highly activated effector memory CD8 T (EM) cells, regardless of antigen specificity. This robust activation is associated with key features of early T cell exhaustion including a loss in polyfunctional type-1 cytokine production and partial commitment to type-2 cells. In addition, we show that bystander activation of EM cells seems to be dependent on the inflammatory cytokines IL-15 and IL-18, and is supported by an upregulation of the activating receptor NKG2D and an exuberant expression of T-Bet and T-Bet-regulated genes including granzyme B and CXCR3. We also show that the inflammatory chemokines CXCL9-10 are increased in symptomatic patients thereby fostering the recruitment of highly cytotoxic EM cells into the liver in a CXCR3-dependent manner. Finally, we find that the EM-biased immune response returns to homeostasis following viral clearance and disease resolution, further linking the EM cells response to viral burden. Conversely, asymptomatic patients are endowed with low-to-moderate EM cell response. In summary, our findings define immune correlates that contribute to HEV-3 pathogenesis and emphasize the central role of EM cells in governing the outcome of the infection.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33053331,

title = {Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8 T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy},

author = {Marianne Weulersse and Assia Asrir and Andrea C Pichler and Lea Lemaitre and Matthias Braun and Nadège Carrié and Marie-Véronique Joubert and Marie Le Moine and Laura Do Souto and Guillaume Gaud and Indrajit Das and Elisa Brauns and Clara M Scarlata and Elena Morandi and Ashmitha Sundarrajan and Marine Cuisinier and Laure Buisson and Sabrina Maheo and Sahar Kassem and Arantxa Agesta and Michaël Pérès and Els Verhoeyen and Alejandra Martinez and Julien Mazieres and Loïc Dupré and Thomas Gossye and Vera Pancaldi and Camille Guillerey and Maha Ayyoub and Anne S Dejean and Abdelhadi Saoudi and Stanislas Goriely and Hervé Avet-Loiseau and Tobias Bald and Mark J Smyth and Ludovic Martinet},

doi = {10.1016/j.immuni.2020.09.006},

issn = {1097-4180},

year  = {2020},

date = {2020-10-01},

urldate = {2020-10-01},

journal = {Immunity},

volume = {53},

number = {4},

pages = {824--839.e10},

abstract = {CD8 T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8 T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8 T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226 CD8 T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8 tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226 mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8 T cell function and limits the efficacy of cancer immunotherapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31776254,

title = {Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation},

author = {Ulf Gehrmann and Marianne Burbage and Elina Zueva and Christel Goudot and Cyril Esnault and Mengliang Ye and Jean-Marie Carpier and Nina Burgdorf and Thomas Hoyler and Guadalupe Suarez and Leonel Joannas and Sandrine Heurtebise-Chrétien and Sylvère Durand and Rébecca Panes and Angélique Bellemare-Pelletier and Pablo J Sáez and Fanny Aprahamian and Deborah Lefevre and Veronique Adoue and Amal Zine El Aabidine and Maqbool Muhammad Ahmad and Claire Hivroz and Olivier Joffre and Florence Cammas and Guido Kroemer and Etienne Gagnon and Jean-Christophe Andrau and Sebastian Amigorena},

doi = {10.1073/pnas.1901639116},

issn = {1091-6490},

year  = {2019},

date = {2019-12-01},

urldate = {2019-12-01},

journal = {Proc Natl Acad Sci U S A},

volume = {116},

number = {51},

pages = {25839--25849},

abstract = {Naive CD4 T lymphocytes differentiate into different effector types, including helper and regulatory cells (Th and Treg, respectively). Heritable gene expression programs that define these effector types are established during differentiation, but little is known about the epigenetic mechanisms that install and maintain these programs. Here, we use mice defective for different components of heterochromatin-dependent gene silencing to investigate the epigenetic control of CD4 T cell plasticity. We show that, upon T cell receptor (TCR) engagement, naive and regulatory T cells defective for TRIM28 (an epigenetic adaptor for histone binding modules) or for heterochromatin protein 1 β and γ isoforms (HP1β/γ, 2 histone-binding factors involved in gene silencing) fail to effectively signal through the PI3K-AKT-mTOR axis and switch to glycolysis. While differentiation of naive TRIM28 T cells into cytokine-producing effector T cells is impaired, resulting in reduced induction of autoimmune colitis, TRIM28 regulatory T cells also fail to expand in vivo and to suppress autoimmunity effectively. Using a combination of transcriptome and chromatin immunoprecipitation-sequencing (ChIP-seq) analyses for H3K9me3, H3K9Ac, and RNA polymerase II, we show that reduced effector differentiation correlates with impaired transcriptional silencing at distal regulatory regions of a defined set of Treg-associated genes, including, for example, NRP1 or Snai3. We conclude that TRIM28 and HP1β/γ control metabolic reprograming through epigenetic silencing of a defined set of Treg-characteristic genes, thus allowing effective T cell expansion and differentiation into helper and regulatory phenotypes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30737147,

title = {The Histone Methyltransferase SETDB1 Controls T Helper Cell Lineage Integrity by Repressing Endogenous Retroviruses},

author = {Véronique Adoue and Bénédicte Binet and Agathe Malbec and Joanna Fourquet and Paola Romagnoli and Joost P M van Meerwijk and Sebastian Amigorena and Olivier P Joffre},

doi = {10.1016/j.immuni.2019.01.003},

issn = {1097-4180},

year  = {2019},

date = {2019-03-01},

urldate = {2019-03-01},

journal = {Immunity},

volume = {50},

number = {3},

pages = {629--644.e8},

abstract = {Upon activation, naive CD4 T cells differentiate into distinct T cell subsets via processes reliant on epigenetically regulated, lineage-specific developmental programs. Here, we examined the function of the histone methyltransferase SETDB1 in T helper (Th) cell differentiation. Setdb1 naive CD4 T cells exhibited exacerbated Th1 priming, and when exposed to a Th1-instructive signal, Setdb1 Th2 cells crossed lineage boundaries and acquired a Th1 phenotype. SETDB1 did not directly control Th1 gene promoter activity but relied instead on deposition of the repressive H3K9me3 mark at a restricted and cell-type-specific set of endogenous retroviruses (ERVs) located in the vicinity of genes involved in immune processes. Refined bioinformatic analyses suggest that these retrotransposons regulate Th1 gene cis-regulatory elements or act as Th1 gene enhancers. Thus, H3K9me3 deposition by SETDB1 ensures Th cell lineage integrity by repressing a repertoire of ERVs that have been exapted into cis-regulatory modules to shape and control the Th1 gene network.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}