Negative Regulation of NKG2D Expression by IL-4 in Memory CD8 T Cells

International audienceIL-4 is one of the main cytokines produced during Th2-inducing pathologies. This cytokine has been shown to affect a number of immune processes such as Th differentiation and innate immune responses. However, the impact of IL-4 on CD8 T cell responses remains unclear. In this study, we analyzed the effects of IL-4 on global gene expression profiles of Ag-induced memory CD8 T cells in the mouse. Gene ontology analysis of this signature revealed that IL-4 regulated most importantly genes associated with immune responses. Moreover, this IL-4 signature overlapped with the set of genes preferentially expressed by memory CD8 T cells over naive CD8 T cells. In particular, IL-4 downregulated in vitro and in vivo in a STAT6-dependent manner the memory-specific expression of NKG2D, thereby increasing the activation threshold of memory CD8 T cells. Furthermore, IL-4 impaired activation of memory cells as well as their differentiation into effector cells. This phenomenon could have an important clinical relevance as patients affected by Th2 pathologies such as parasitic infections or atopic dermatitis often suffer from viral-induced complications possibly linked to inefficient CD8 T cell responses

Functions and plasticity of inflammatory memory CD8 T cells

Les LT CD8 mémoires constituent une population hétérogène. Une modulation des différents signaux d’activation des LT CD8 naïfs influe sur la diversité des LT CD8 effecteurs et mémoires générés. A coté des sous populations classiquement décrites de LT CD8 mémoires développés dans des conditions infectieuses, il existe une population de LT CD8 mémoires générés dans des conditions d’inflammation stérile, c’est-à-dire en absence de pathogènes et de signaux moléculaires dérivés de pathogènes : les TIM pour « T-inflammatory memory cells ». Au cours de cette thèse j’ai eu pour objectif : 1) de mieux caractériser la population de TIM 2) d’évaluer leur capacité à répondre à une activation par un pathogène viral et ainsi leur plasticité et 3) d’étudier leur recrutement au site d’une infection locale respiratoire.J’ai ainsi pu identifier de nouvelles propriétés des TIM et montrer que les TIM sont recrutés dans une réponse secondaire à un virus exprimant la même spécificité antigénique, en générant des LT CD8 mémoires secondaires aux fonctions améliorées. De plus, les LT CD8 mémoires secondaires générés présentent un avantage fonctionnel par rapport aux LT CD8 mémoires primaires dans leur capacité de production de TNF-α et de la chimiokine XCL1. Cette dernière propriété pourrait leur conférer un avantage pour la réponse à des antigènes cross présentés. J’ai par ailleurs montré la capacité des TIM à être recrutés au niveau du poumon et des voies aériennes au cours d’une infection respiratoire virale. Ces résultats montrent que les LT CD8 mémoires générés dans des conditions d’activation inflammatoires stériles peuvent prendre part au contingent de cellules immunitaires impliquées dans des réponses à des infections. Ces résultats ouvrent un champ d’investigation intéressant concernant la plasticité des LT CD8 mémoires. Ils pourraient avoir une incidence sur certaines pathologies inflammatoires, dans le cas d’une ré-activation des TIM par un virus cross réactif.Memory CD8 T cells represent a heterogeneous population. A modulation of the activation signals during naïve CD8 T cells activation influences the diversity of the Effector and Memory CD8 T cells generated. Besides the classically described subsets of Memory CD8 T cells, generated under infectious conditions, are T inflammatory memory CD8 T cells (TIM). TIM are generated under sterile priming conditions that are devoid of pathogens and pathogen-derived danger signals.During this thesis, I had the latter objectives: 1) a better characterisation of TIM, 2) to evaluate whether they could be recruited in an immune response directed against a virus and thus investigate their plasticity, 3) to examine their recruitment to the site of a respiratory local infection.I have identified new features of TIM and shown that TIM can take part to the immune response triggered by a virus expressing their cognate antigen and further differentiate into secondary memory cells with improved functions. The secondary memory CD8 T cells they generate display a functional advantage over primary memory cells in their capacity to produce TNF-α and the XCL1 chemokine. This last result could give them an advantage against cross-presented antigen. Furthermore, I have shown that TIM cells can be recruited in lung and airways during a respiratory viral infection. These results show that memory CD8 T cells generated under sterile priming conditions can take part to the contingent of immune cells involved in responses to infection. They open an interesting field of investigation of the plasticity of memory CD8 T cells. They could have an impact in inflammatory diseases, in the case of re-activation of TIM by a cross-reactive virus

Fonctions et plasticité des LT CD8 mémoires inflammatoires

Les LT CD8 mémoires constituent une population hétérogène. Une modulation des différents signaux d activation des LT CD8 naïfs influe sur la diversité des LT CD8 effecteurs et mémoires générés. A coté des sous populations classiquement décrites de LT CD8 mémoires développés dans des conditions infectieuses, il existe une population de LT CD8 mémoires générés dans des conditions d inflammation stérile, c est-à-dire en absence de pathogènes et de signaux moléculaires dérivés de pathogènes: les TIM pour T-inflammatory memory cells . Au cours de cette thèse j ai eu pour objectif: 1) de mieux caractériser la population de TIM 2) d évaluer leur capacité à répondre à une activation par un pathogène viral et ainsi leur plasticité et 3) d étudier leur recrutement au site d une infection locale respiratoire.J ai ainsi pu identifier de nouvelles propriétés des TIM et montrer que les TIM sont recrutés dans une réponse secondaire à un virus exprimant la même spécificité antigénique, en générant des LT CD8 mémoires secondaires aux fonctions améliorées. De plus, les LT CD8 mémoires secondaires générés présentent un avantage fonctionnel par rapport aux LT CD8 mémoires primaires dans leur capacité de production de TNF-a et de la chimiokine XCL1. Cette dernière propriété pourrait leur conférer un avantage pour la réponse à des antigènes cross présentés. J ai par ailleurs montré la capacité des TIM à être recrutés au niveau du poumon et des voies aériennes au cours d une infection respiratoire virale. Ces résultats montrent que les LT CD8 mémoires générés dans des conditions d activation inflammatoires stériles peuvent prendre part au contingent de cellules immunitaires impliquées dans des réponses à des infections. Ces résultats ouvrent un champ d investigation intéressant concernant la plasticité des LT CD8 mémoires. Ils pourraient avoir une incidence sur certaines pathologies inflammatoires, dans le cas d une ré-activation des TIM par un virus cross réactif.Memory CD8 T cells represent a heterogeneous population. A modulation of the activation signals during naïve CD8 T cells activation influences the diversity of the Effector and Memory CD8 T cells generated. Besides the classically described subsets of Memory CD8 T cells, generated under infectious conditions, are T inflammatory memory CD8 T cells (TIM). TIM are generated under sterile priming conditions that are devoid of pathogens and pathogen-derived danger signals.During this thesis, I had the latter objectives: 1) a better characterisation of TIM, 2) to evaluate whether they could be recruited in an immune response directed against a virus and thus investigate their plasticity, 3) to examine their recruitment to the site of a respiratory local infection.I have identified new features of TIM and shown that TIM can take part to the immune response triggered by a virus expressing their cognate antigen and further differentiate into secondary memory cells with improved functions. The secondary memory CD8 T cells they generate display a functional advantage over primary memory cells in their capacity to produce TNF-a and the XCL1 chemokine. This last result could give them an advantage against cross-presented antigen. Furthermore, I have shown that TIM cells can be recruited in lung and airways during a respiratory viral infection. These results show that memory CD8 T cells generated under sterile priming conditions can take part to the contingent of immune cells involved in responses to infection. They open an interesting field of investigation of the plasticity of memory CD8 T cells. They could have an impact in inflammatory diseases, in the case of re-activation of TIM by a cross-reactive virus.LYON-ENS Sciences (693872304) / SudocSudocFranceF

An impulse oscillometry system is less efficient than spirometry in tracking lung function improvements after intravenous antibiotic therapy in pediatric patients with cystic fibrosis

International audienceA literature search identified one retrospective study on the responsiveness of impulse oscillometry (IOS) in pediatric patients with cystic fibrosis. The aim of this prospective observational study was to assess this property in an adequately powered study after intravenous antibiotic therapy (IVAT) administered for an acute episode of pulmonary exacerbation. Spirometry and IOS were done on the same day as the start and the end of IVAT. Data from 34 patients’ of mean age 11.9 years (range, 5–17 years) were studied. The mean FEV1 at the start and at the end of the IVAT was 73.1 ± 23.8% (range, 23.4–122%) and 88.3 ± 21.3% (range, 29.4–131%), respectively. The mean relative change (mean ± SD) was 20.2 ± 14.2% for FEV1 (ΔFEV1), −21.9 ± 23.8% for reactance at 5 Hz (ΔX5) and –13.4 ± 18.9% for resistance at 5 Hz (Δ R5) (all P-values <0.05). There was a weak but significant correlation between ΔFEV1 and ΔX5 (r =–0.473; p = 0.01). The magnitude of improvement of ΔX5 was not statistically different between patients with normal versus abnormal lung function at the start of IVAT. Furthermore, using ΔX5 alone as an outcome measure of IVAT efficiency resulted in a significant improvement in 44% of the patients, while it was 79% with ΔFEV1. These results indicate that IOS may track changes after IVAT, but that this improvement may be insufficiently evaluated using IOS alone

T inflammatory memory CD8 T cells participate to antiviral response and generate secondary memory cells with an advantage in XCL1 production

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Factors Associated with Asthma Severity in Children: Data from the French COBRAPed Cohort

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The grapevine genome sequence suggests ancestral hexaploidization in major angiosperm phyla.

International audienceThe analysis of the first plant genomes provided unexpected evidence for genome duplication events in species that had previously been considered as true diploids on the basis of their genetics. These polyploidization events may have had important consequences in plant evolution, in particular for species radiation and adaptation and for the modulation of functional capacities. Here we report a high-quality draft of the genome sequence of grapevine (Vitis vinifera) obtained from a highly homozygous genotype. The draft sequence of the grapevine genome is the fourth one produced so far for flowering plants, the second for a woody species and the first for a fruit crop (cultivated for both fruit and beverage). Grapevine was selected because of its important place in the cultural heritage of humanity beginning during the Neolithic period. Several large expansions of gene families with roles in aromatic features are observed. The grapevine genome has not undergone recent genome duplication, thus enabling the discovery of ancestral traits and features of the genetic organization of flowering plants. This analysis reveals the contribution of three ancestral genomes to the grapevine haploid content. This ancestral arrangement is common to many dicotyledonous plants but is absent from the genome of rice, which is a monocotyledon. Furthermore, we explain the chronology of previously described whole-genome duplication events in the evolution of flowering plants