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Understanding the heterogeneity of human CD4+FOXP3+ regulatory T cells (Tregs) and their potential for lineage reprogramming is of critical importance for moving Treg therapy into the clinics. Using multiparameter single-cell analysis techniques, we explored the heterogeneity and functional diversity of human Tregs in healthy donors and in patients after allogeneic hematopoietic stem cell transplantation (alloHSCT). Human Tregs displayed a level of complexity similar to conventional CD4+ effector T cells with respect to the expression of transcription factors, homing receptors and inflammatory cytokines. Single-cell profiling of the rare Treg producing interleukin-17A or interferon-γ showed an overlap of gene expression signatures of Th17 or Th1 cells and of Tregs. To assess whether Treg homeostasis is affected by an inflammatory and lymphopenic environment, we characterized the Treg compartment in patients early after alloHSCT. This analysis suggested a marked depletion of Treg with a naive phenotype in patients developing acute graft-versus-host disease, compared with tolerant patients. However, single-cell profiling showed that CD4+FOXP3+ T cells maintain the Treg gene expression signature and Treg-suppressive activity was preserved. Our study establishes that heterogeneity at the single-cell level, rather than lineage reprogramming of CD4+FOXP3+ T cells, explains the remarkable complexity and functional diversity of human Tregs.

Janin Y.L.,Institute Pasteur Paris | Janin Y.L.,French National Center for Scientific Research
Chemical Reviews | Year: 2012

A pyrazole nucleus halogenation, if possible regioselective, is often the first step of many syntheses of more elaborated derivatives. Concerning the preparation of 3/5-halogenated derivatives with electrophilic reagents, this usually requires the 4 position to be substituted. Otherwise, halogenation will first take place on position 4 and then on the other ones, usually at higher temperature and/or using stronger reaction conditions. One approach to avoid the faster 4-halogenation of pyrazoles is to undertake C-5 halogenation of suitably N-substituted pyrazole anions. Dehydroxyhalogenation of 3/5-hydroxypyrazoles is probably one of the most obvious preparations of 3/5-chloro- or 3/5- bromopyrazoles using reagents such as phosphorus oxychloride or phosphorus oxybromide. Preparation of 1-substituted 3-halogenopyrazoles by the Sandmeyer reaction is also possible. Cycloaddition between sydnones and halogenated dipole leads to 3-halogenopyrazoles.

Dillies M.-A.,Institute Pasteur Paris
Briefings in Bioinformatics | Year: 2013

During the last 3 years, a number of approaches for the normalization of RNA sequencing data have emerged in the literature, differing both in the type of bias adjustment and in the statistical strategy adopted.However, as data continue to accumulate, there has been no clear consensus on the appropriate normalization method to be used or the impact of a chosen method on the downstream analysis. In this work, we focus on a comprehensive comparison of seven recently proposed normalization methods for the differential analysis of RNA-seq data, with an emphasis on the use of varied real and simulated datasets involving different species and experimental designs to represent data characteristics commonly observed in practice. Based on this comparison study, we propose practical recommendations on the appropriate normalization method to be used and its impact on the differential analysis of RNA-seq data. © The Author 2012. Published by Oxford University Press.

Koonin E.V.,U.S. National Center for Biotechnology Information | Krupovic M.,Institute Pasteur Paris
Nature Reviews Genetics | Year: 2015

Adaptive immune systems in prokaryotes and animals give rise to long-term memory through modification of specific genomic loci, such as by insertion of foreign (viral or plasmid) DNA fragments into clustered regularly interspaced short palindromic repeat (CRISPR) loci in prokaryotes and by V(D)J recombination of immunoglobulin genes in vertebrates. Strikingly, recombinases derived from unrelated mobile genetic elements have essential roles in both prokaryotic and vertebrate adaptive immune systems. Mobile elements, which are ubiquitous in cellular life forms, provide the only known, naturally evolved tools for genome engineering that are successfully adopted by both innate immune systems and genome-editing technologies. In this Opinion article, we present a general scenario for the origin of adaptive immunity from mobile elements and innate immune systems. © 2015 Macmillan Publishers Limited.

Etienne-Manneville S.,Institute Pasteur Paris
Current Opinion in Cell Biology | Year: 2010

Microtubules are highly dynamic structures whose regulation is crucial for cell division, cell polarity, cell migration, or neuronal differentiation. Because they contribute to most cellular functions, they must be regulated in response to extracellular and intracellular signals. The parameters of microtubule dynamics are numerous and complex and the connection between signaling pathways and regulation of microtubule dynamics remain obscure. Recent observations reveal key players that can both integrate the diversity of signaling cascades and directly influence microtubule dynamics. I review here how modifications of the tubulin dimer, tubulin modifying enzymes, and microtubule-associated proteins are directly involved in the regulation of microtubule behavior and functions. © 2009 Elsevier Ltd. All rights reserved.

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