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Bourses 2017

  • Bourse de voyage attribue
Michael Michieletto Inserm UMR1043 - CNRS UMR5282 - Universit Toulouse III CHU Purpan - Toulouse pour sa participation au congrs de l'"American Association of Immunologists" qui s'est tenu Washington DC du 12 au 18 mai 2017.

Son rsum 'Foxo3 Transcription Factor drives pathogenic T Helper 1 differentiation by inducing the expression of Eomes’ a t slectionn en communication orale :


CD4 T cell differentiation is a process finely controlled by specific transcriptional programs leading to the acquisition of specific T helper effector functions. Up to now, the functions of Foxo3 in CD4 T cells have not been investigate. Here, we described for the first time the critical role of the transcription factors Foxo3 in Eomes expression and their involvement in pathogenic T Helper 1 differentiation.
First, we showed that TCR triggering resulted in a dose-dependent upregulation of Foxo3 in CD4 T cells with an increased expression over time. We next addressed Foxo3 functions in CD4 T cells and we observed a decreased production of the Th1 related cytokines IFN-γ and GM-CSF by Foxo3 KO CD4 T cells, with no impact survival, proliferation or other lineages differentiation. We then compared the transcriptome of WT and Foxo3 KO CD4 T cells and found that Foxo3 deficiency resulted in a decreased expression of genes related to the IFN- γ /IFN-γ response pathway and that the most downregulated gene in this pathway is Eomes. We showed, using ChIP and luciferase experiments, that Foxo3 binds and induces the expression of Eomes through direct DNA binding within the eomes locus. Using lentivirus experiments we showed overexpression of Eomes in Foxo3 KO CD4 T cell restored the proportion of IFN-γ and GM-CSF producing cells, thus comforting Eomes role’s in the pathogenicity of CD4 T cells. In addition to this defect of differentiation, Foxo3-deficient mice developed a less severe Experimental Autoimmune Encephalomyelitis (EAE) as compared to WT mice, thus emphasizing the role of Foxo3 and Eomes in the development of autoimmunity. Altogether, we described here a new pathway whereby Foxo3 and Eomes drive CD4 T cells pathogenicity and neuro-inflammation.




  • Bourse de voyage attribue
Dylan CHERRIER - Etudiant en thse- Unit d'Immunit Inne - Institut Pasteur pour sa participation l'ENII Summer School 2017 qui s'est tenu Porto Cervo, en Sardaigne du 16 au 13 mai 2017.

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La Summer School organise par l'ENII (European Network of Immunology Institutes) s'est droule cette anne du 6 au 13 mai, l'htel Le Ginestre de Porto Cervo, en Sardaigne. Les matins taient rservs des cours de haut niveau dispenss par des chercheurs titulaires venus de toute l'Europe, tandis que les aprs-midi taient consacrs aux prsentations courtes de travaux raliss par les tudiants. Enfin, les dbuts de soires permettaient des changes plus informels avec les chercheurs au cours de sessions tutores, et les soirs permettaient d'avoir une vision globale des travaux des tudiants via la prsentation de posters, obligatoire pour chaque tudiant cette anne (y compris ceux ayant obtenu une prsentation orale). Le sixime jour tait quant lui rserv un vnement davantage social, une excursion en bateau sur les les environnantes.
Cette Summer School restera pour moi une exprience formidable, et ce pour plusieurs raisons. Tout d'abord, c'tait ma premire occasion de communiquer mes rsultats l'oral devant un auditoire dpassant le cadre du laboratoire. Cela m'a permis bien sr de pratiquer et de travailler mes comptences de communication, mais cela m'a surtout permis d'avoir des conversations extrmement enrichissantes le soir-mme, lors de la prsentation du poster, avec des participants intresss par mon domaine de recherche et pleins de suggestions. Cet environnement m'a galement permis de lever certaines barrires, et d'oser beaucoup plus facilement poser des questions lors des prsentations. J'ai galement pu changer en tte--tte avec certains chercheurs titulaires, ce qui aurait sans doute t beaucoup plus difficile pour moi lors d'un congrs plus classique. La qualit scientifique de cette cole m'a aussi permis de prendre du recul sur mes propres travaux, et d'avoir une vue plus globale non seulement du domaine de l'immunologie, mais galement de mon propre domaine de travail, les cellules lymphodes innes. Pour terminer, cette cole d't aura surtout t l'occasion de rencontrer des personnes formidables, avec qui j'en suis sr je pourrai garder contact, qui m'ont apport et qui je l'espre m'apporteront encore tant sur le plan personnel que professionnel.
En conclusion, je souhaite remercier la Socit Franais d'Immunologie pour son soutien ma participation l'ENII Summer School, et je souhaite encourager tout jeune chercheur membre de la socit se rendre galement cette cole dans les annes avenir, tant j'en ai t moi-mme satisfait.




  • Bourse de voyage attribue

Silvia Menegatti Institut Pasteur - Paris pour sa participation au congrs " Fundamental Immunology & Its Therapeutic Potential meeting" qui s'est tenu Cold Spring Harbor, NY du 25 au 28 avril 2017.

Meeting report

The “Fundamental immunology and its therapeutic potential” meeting has been held from April 25th to April 29th in Cold Spring Harbor, New York. The meeting, coorganized by Eric Pamer, Fiona Powrie and Stephane Smale, has been divided in 10 sessions involving the major research topics in immunology. Two of these sessions have been dedicated to poster presentation, the others consisted of oral presentations. The main aim of the meeting was to enhance fundamental immunology research while speeding the translation of basic immunology discoveries to the clinic. All the authors highlighted the importance of strong interactions between basic and translational researchers and the importance of developing new immune therapies for the treatment of cancer, infectious diseases, autoimmune and inflammatory disorders.
The majority of the talks focused on anti-tumor immunity and in particular on the mechanism of immune checkpoints blockade. Lyndsay Avery, PhD student in the lab of Dr. Kane at the University of Pittsburgh, presented the role of Tim-3 in T cell exhaustion and memory. T cell exhaustion is the progressive lost of T cell function, which occurs in settings of chronic viral infection and in the tumor microenvironment. T cell exhaustion is mediated by several inhibitory receptors including PD-1, CTLA-4, LAG-3 and Tim-3. While the first 3 checkpoint receptors have known mechanisms for reducing T cell effector function, the intrinsic effects of Tim-3 on T cell activation are largely unknown. During this presentation, it has been shown that there is no evident effect of Tim-3 overexpression on the development of T cell exhaustion in a LCMV infection model. However, lack of Tim-3 (using Tim-3 KO mice) resulted in a reduced ability of T cells to respond to chronic viral infections. Furthermore, it has been demonstrated that the overexpression of Tim-3 leads to an increase of short-lived effector T cells. Therefore, Tim-3 is essential for an optimal effector T cell response, but may contribute to exhaustion by restricting development of long-lived memory T cells.
During the same session on anti-tumor immunity, Michael Sadelain, PhD at the Memorial Sloan Kettering Cancer Center, presented his recent study on CRISPR/CAS9-targeted chimeric antigen receptor, able to enhance CAR T-cell mediated tumor eradication. Chimeric antigen receptors (CARs) are synthetic receptors that redirect and reprogram T cells to mediate tumor rejection. The most successful CARs used to date are those targeting CD19, which offer the prospect of complete remissions in patients with chemorefractory/relapsed B cell malignancies. They have used CRISPR/Cas9 to edit human T cells. In particular, it has been shown that directing a CD19 CAR to the human T cell receptor (TCR) alpha chain (TRAC) locus not only resulted in efficient and uniform CAR expression in human peripheral blood T cells, but, remarkably, also enhances T cell potency. They have further showed that CAR gene expression under the control of the TCR alpha promoter minimizes tonic signaling and allows effective regulation of CAR expression.
Still in the context of cancer immunotherapy, Alan Hanash, MD, PhD at the Memorial Sloan Kettering Cancer Center of New York has talked about one potential therapy for graft vs. host disease (GVHD), one of the most common complications after allogeneic hematopoietic transplantation. Hanash and colleagues have investigated the role of intestinal stem cells (ISCs) after bone marrow transplantation and found that this cell population was lost in experimental GVHD. Furthermore, they have demonstrated that IL-22, mainly derived from type 3 innate lymphoid cells, was important for protecting the ISC compartment post-transplantation. In GVHD, the alloreactive donor immune response leads to the elimination of the recipients’ IL-22 producing cells. Thus, treatment with IL-22 in these settings may be able to overcome the loss of ILCs and promote epithelial regeneration. In mice treated with IL-22, the authors observed an improvement in tissue recovery during active GVHD. Seen the promising results in mice, IL-22 treatment for GVHD is now in phase II clinical trials and will be hopefully soon available for more patients.
Another important topic discussed during the meeting was the role of the microbiota on the immune system. A former post-doc in Yasmine Belkaide lab, Tymothy Hand, now becoming an independent investigator at the Pittsburgh University, has shown how the mucosal environment is shaped by the microbiota in the gastrointestinal tract. The work of Hand and colleagues focused on how T and B cells respond to novel interactions with the individual bacteria within the microbiota. They have studied the immune system in the first days of bacterial colonization post birth, when organisms first encounter a host whose immune system has no experience with microbes. Specifically, they have recruited a cohort of patients affected by necrotizing enterocolitis (NEC), the second leading cause of death in premature children. Previous studies showed that feeding children with breast milk reduces the incidence of the disease. The authors demonstrated that IgA+ B cells in breast milk, binding to invasive intestinal bacteria, were protective against the risk of developing NEC. Breastfeeding, compared to formula feeding, is more enriched in IgA. At this early time point, maternal antibody is critical in shaping the configuration and behavior of the microbiota and may play a critical role in preventing immune responses and inflammatory disease.
The two poster sessions have been also very interesting. Samuele Notarbartolo, post-doc in the lab of Federica Sallusto, at the Institute for Research in Biomedicine, Bellinzona, Switzerland, has shown the role of IL10-producing Th17 cells in mice andhuman. Using genome-wide gene expression analysis and chromatin immunoprecipitation assays, Notarbartolo and colleagues have identified genes that are differentially expressed in IL-10+ and IL-10- Th17 cells and investigated the mechanisms by which these genes are transcriptionally regulated. Several genes highly expressed in IL-10- Th17 cells have been associated with “pathogenic” mouse Th17 or have been linked to pro-inflammatory immune responses. In contrast, genes highly expressed in IL-10+ Th17 cells have been associated with “non-pathogenic” mouse Th17 cells and also expressed high levels of the transcription factor c-MAF. Notably, c-MAF was found to bind many of the genes differentially expressed in IL-10+ vs. IL-10- Th17 cells and extensively bound bona fide enhancers in activated IL-10+ Th17 cells. The authors demonstrated that c-MAF represents a relevant factordiscriminating between pathogenic and non-pathogenic human Th17 cells.



  • Bourse de voyage attribue
Maria Matias IGMM UMR5535 CNRS - Montpellier pour sa participation au congrs du FOCIS qui s'est tenu Chicago du 14 au 17 juin 2017. Suite aux nominations de la SFI, une bourse a t lui attribue par le FOCIS, bourse double par la SFI selon les termes de l'appel d'offre.

Son rsum 'Rgulation mtabolique de l’immunit des lymphocytes T humains’ a t slectionn en communication orale :

L’activation des lymphocytes T est rgule par le mtabolisme du glucose, des acides gras et acides amins, qui soutiennent les besoins nergtiques et biosynthtiques de la cellule. Nous avons prcdemment dmontr que la disponibilit en nutriment rgule la diffrenciation des cellules T CD4 murines effectrices. L’activation des cellules murine T naves en condition limitante en glutamine conduit leur diffrenciation en cellules T rgulatrices Foxp3+ (Treg) ayant des fonctions suppressives efficaces in vivo, et inhibe leur diffrenciation en cellules Th1(Klysz et al., 2015). Nous montrons maintenant que les cellules T CD4+ et CD8+ humaines sont significativement plus sensibles la teneur extracellulaire en glutamine par rapport au glucose, et qu’une carence en glutamine, diminue fortement leur prolifration et s’accompagne d’un dfaut du niveau d’expression en surface de transporteurs de nutriments. De plus, alors que la capacit des lymphocytes T produite de l’IL2 n’est pas fortement impacte par une carence en glutamine, la production d’IFNg est diminue de 5-10 fois. Notamment, l’augmentation dans le cycle de Krebs, d’intermdiaires mtaboliques issus de la glutamine, augmente le potentiel de transport de nutriments des cellules T humaines et iSTLS inhibe leur diffrenciation en Tregs. Ainsi, la disponibilit en nutriments et les mtabolites en dcoulant peuvent tre utiliss pour moduler le processus de diffrenciation des cellules T et la rponse immunitaire.
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