Limited Foxp3+ Regulatory T Cells Response During Acute Trypanosoma cruzi Infection Is Required to Allow the Emergence of Robust Parasite-Specific CD8+ T Cell Immunity

While it is now acknowledged that CD4+ T cells expressing CD25 and Foxp3 (Treg cells) regulate immune responses and, consequently, influence the pathogenesis of infectious diseases, the regulatory response mediated by Treg cells upon infection by Trypanosoma cruzi was still poorly characterized. In order to understand the role of Treg cells during infection by this protozoan parasite, we determined in time and space the magnitude of the regulatory response and the phenotypic, functional and transcriptional features of the Treg cell population in infected mice. Contrary to the accumulation of Treg cells reported in most chronic infections in mice and humans, experimental T. cruzi infection was characterized by sustained numbers but decreased relative frequency of Treg cells. The reduction in Treg cell frequency resulted from a massive accumulation of effector immune cells, and inversely correlated with the magnitude of the effector immune response as well as with emergence of acute immunopathology. In order to understand the causes underlying the marked reduction in Treg cell frequency, we evaluated the dynamics of the Treg cell population and found a low proliferation rate and limited accrual of peripheral Treg cells during infection. We also observed that Treg cells became activated and acquired a phenotypic and transcriptional profile consistent with suppression of type 1 inflammatory responses. To assess the biological relevance of the relative reduction in Treg cells frequency observed during T. cruzi infection, we transferred in vitro differentiated Treg cells at early moments, when the deregulation of the ratio between regulatory and conventional T cells becomes significant. Intravenous injection of Treg cells dampened parasite-specific CD8+ T cell immunity and affected parasite control in blood and tissues. Altogether, our results show that limited Treg cell response during the acute phase of T. cruzi infection enables the emergence of protective anti-parasite CD8+ T cell immunity and critically influences host resistance

Long-Range Enhancer Associated with Chromatin Looping Allows AP-1 Regulation of the Peptidylarginine Deiminase 3 Gene in Differentiated Keratinocyte

Transcription control at a distance is a critical mechanism, particularly for contiguous genes. The peptidylarginine deiminases (PADs) catalyse the conversion of protein-bound arginine into citrulline (deimination), a critical reaction in the pathophysiology of multiple sclerosis, Alzheimer's disease and rheumatoid arthritis, and in the metabolism of the major epidermal barrier protein filaggrin, a strong predisposing factor for atopic dermatitis. PADs are encoded by 5 clustered PADI genes (1p35-6). Unclear are the mechanisms controlling the expression of the gene PADI3 encoding the PAD3 isoform, a strong candidate for the deimination of filaggrin in the terminally differentiating epidermal keratinocyte. We describe the first PAD Intergenic Enhancer (PIE), an evolutionary conserved non coding segment located 86-kb from the PADI3 promoter. PIE is a strong enhancer of the PADI3 promoter in Ca2+-differentiated epidermal keratinocytes, and requires bound AP-1 factors, namely c-Jun and c-Fos. As compared to proliferative keratinocytes, calcium stimulation specifically associates with increased local DNase I hypersensitivity around PIE, and increased physical proximity of PIE and PADI3 as assessed by Chromosome Conformation Capture. The specific AP-1 inhibitor nordihydroguaiaretic acid suppresses the calcium-induced increase of PADI3 mRNA levels in keratinocytes. Our findings pave the way to the exploration of deimination control during tumorigenesis and wound healing, two conditions for which AP-1 factors are critical, and disclose that long-range transcription control has a role in the regulation of the gene PADI3. Since invalidation of distant regulators causes a variety of human diseases, PIE results to be a plausible candidate in association studies on deimination-related disorders or atopic disease

Identification, Replication, and Fine-Mapping of Loci Associated with Adult Height in Individuals of African Ancestry

Adult height is a classic polygenic trait of high heritability (h2 ∼0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain ∼10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10−12 and 2p14-rs4315565, P = 1.2×10−8). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10−4 for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits

Les rétrovirus endogènes : un rôle clef dans la programmation des lymphocytes T CD4

International audienc

Le contrôle de l'expression des peptidyl-aginine désiminases dans les kératinocytes associe des éléments proximaux et une région intergénique distante, et implique les facteurs AP-1 c-Jun, c-Fos et JunD (un modèle d'étude de la différenciation terminale épidermique)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Les rétrovirus endogènes : un rôle clé dans la programmation des lymphocytes T CD4

International audienceUpon priming by dendritic cells, naïve CD4 T lymphocytes are exposed to distinct molecular environments depending on the nature of the pathological stimulus. In response, they mobilize different gene networks that establish lineage-specific developmental programs, and coordinate the acquisition of specific phenotype and functions. Accordingly, CD4 T cells are capable of differentiation into a large variety of functionally-distinct T helper (Th) cell subsets. In this review, we describe the molecular events that control CD4 T cell differentiation at the level of the chromatin. We insist on recent works that have highlighted the key role of H3K9me3-dependent epigenetic mechanisms in the regulation of T cell identity. Interestingly, these pathways shape and control the developmental programs at least in part through the regulation of endogenous retroviruses-derived sequences that have been exapted into cis-regulatory modules of Th genes.Les lymphocytes T CD4 jouent un rôle clé dans le maintien de l’intégrité de l’organisme contre les dangers endogènes et exogènes. Ces cellules représentent donc un espoir thérapeutique majeur dans de nombreuses situations physiopathologiques. Dans cette synthèse, nous discuterons des mécanismes moléculaires qui définissent l’identité et les fonctions de ces cellules en réponse aux signaux de l’environnement. Nous nous intéresserons plus particulièrement aux voies épigénétiques qui coordonnent leur différenciation et leur plasticité. Des données récentes de la littérature suggèrent qu’elles pourraient agir en régulant l’activité de séquences dérivées de rétrovirus endogènes qui auraient été cooptées en modules cis-régulateurs de gènes pour le bénéfice de l’hôte

La désimination ou citrullination

La désimination, aussi nommée citrullination, est une modification post-traductionnelle aux multiples facettes. Elle est impliquée dans de nombreux processus cellulaires physiologiques comme la régulation génique, le développement embryonnaire ou encore la différenciation terminale, mais aussi dans divers mécanismes physiopathologiques liés à des maladies humaines graves, comme la sclérose en plaques ou la polyarthrite rhumatoïde. La désimination, conversion enzymatique dépendante du calcium de peptidyl-arginines en peptidyl-citrullines, entraîne une perte de charge des protéines-substrats, ce qui a des conséquences majeures sur leur conformation, leur stabilité, leurs interactions et donc leurs fonctions. Chez l’homme, il existe cinq isotypes de peptidyl-arginine désiminases (1-4 et 6) présentant une expression tissulaire variable. Ces isotypes sont très homologues et étroitement régulés aux niveaux transcriptionnel et post-transcriptionnel, comme, probablement, par auto-désimination

The Histone Methyltransferase SETDB1 Controls T Helper Cell Lineage Integrity by Repressing Endogenous Retroviruses

International audienceUpon 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