Human and Mouse CD8+CD25+FOXP3+ Regulatory T Cells at Steady State and during Interleukin-2 Therapy

International audienceIn addition to CD4+ regulatory T cells (Tregs), CD8+ suppressor T cells are emerging as an important subset of regulatory T cells. Diverse populations of CD8+ T cells with suppressive activities have been described. Among them, a small population of CD8+CD25+FOXP3+ T cells is found both in mice and humans. In contrast to thymic-derived CD4+CD25+FOXP3+ Tregs, their origin and their role in the pathophysiology of autoimmune diseases (AIDs) are less understood. We report here the number, phenotype, and function of CD8+ Tregs cells in mice and humans, at the steady state and in response to low-dose interleukin-2 (IL-2). CD8+ Tregs represent approximately 0.4 and 0.1% of peripheral blood T cells in healthy humans and mice, respectively. In mice, their frequencies are quite similar in lymph nodes (LNs) and the spleen, but two to threefold higher in Peyer patches and mesenteric LNs. CD8+ Tregs express low levels of CD127. CD8+ Tregs express more activation or proliferation markers such as CTLA-4, ICOS, and Ki-67 than other CD8+ T cells. In vitro, they suppress effector T cell proliferation as well as or even better than CD4+ Tregs. Owing to constitutive expression of CD25, CD8+ Tregs are 20- to 40-fold more sensitive to in vitro IL-2 stimulation than CD8+ effector T cells, but 2–4 times less than CD4+ Tregs. Nevertheless, low-dose IL-2 dramatically expands and activates CD8+ Tregs even more than CD4+ Tregs, in mice and humans. Further studies are warranted to fully appreciate the clinical relevance of CD8+ Tregs in AIDs and the efficacy of IL-2 treatment

GOHTAM: a website for ‘Genomic Origin of Horizontal Transfers, Alignment and Metagenomics’

Motivation: This website allows the detection of horizontal transfers based on a combination of parametric methods and proposes an origin by researching neighbors in a bank of genomic signatures. This bank is also used to research an origin to DNA fragments from metagenomics studies

Pharmacodynamics of regulatory T cells in mice and humans treated with low-dose IL-2

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Editorial:T cell regulation by the environment

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Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune response

microRNA-21 (miR-21) is the most commonly upregulated miRNA in solid tumors. This cancer-associated microRNA (oncomiR) regulates various downstream effectors associated with tumor pathogenesis during all stages of carcinogenesis. In this study, we analyzed the function of miR-21 in noncancer cells of the tumor microenvironment to further evaluate its contribution to tumor progression. We report that the expression of miR-21 in cells of the tumor immune infiltrate, and in particular in macrophages, was responsible for promoting tumor growth. Absence of miR-21 expression in tumor- associated macrophages (TAMs), caused a global rewiring of their transcriptional regulatory network that was skewed toward a proinflammatory angiostatic phenotype. This promoted an antitumoral immune response characterized by a macrophage-mediated improvement of cytotoxic T-cell responses through the induction of cytokines and chemokines, including IL-12 and C-X-C motif chemokine 10. These effects translated to a reduction in tumor neovascularization and an induction of tumor cell death that led to decreased tumor growth. Additionally, using the carrier peptide pH (low) insertion peptide, we were able to target miR-21 in TAMs, which decreased tumor growth even under conditions where miR-21 expression was deficient in cancer cells. Consequently, miR-21 inhibition in TAMs induced an angiostatic and immunostimulatory activation with potential therapeutic implications

A Benchmark of Parametric Methods for Horizontal Transfers Detection

Horizontal gene transfer (HGT) has appeared to be of importance for prokaryotic species evolution. As a consequence numerous parametric methods, using only the information embedded in the genomes, have been designed to detect HGTs. Numerous reports of incongruencies in results of the different methods applied to the same genomes were published. The use of artificial genomes in which all HGT parameters are controlled allows testing different methods in the same conditions. The results of this benchmark concerning 16 representative parametric methods showed a great variety of efficiencies. Some methods work very poorly whatever the type of HGTs and some depend on the conditions or on the metrics used. The best methods in terms of total errors were those using tetranucleotides as criterion for the window methods or those using codon usage for gene based methods and the Kullback-Leibler divergence metric. Window methods are very sensitive but less specific and detect badly lone isolated gene. On the other hand gene based methods are often very specific but lack of sensitivity. We propose using two methods in combination to get the best of each category, a gene based one for specificity and a window based one for sensitivity

Infiltration of γ⁢δ T cells, IL-17+ T cells and FoxP3+ T cells in human breast cancer

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) have a strong prognostic value in various forms of cancers. These data often refer to use of the pan-T cell marker CD3, or the cytotoxic T lymphocyte marker CD8α. However, T cells are a heterogeneous group of cells with a wide array of effector mechanisms ranging from immunosuppression to cytotoxicity. OBJECTIVE: In this study we have investigated the prognostic effects of some unconventional T cell subtypes in breast cancer; γδ T cells, IL-17+ T cells and FoxP3+ T cells (Tregs) in relation to the conventional CD3 and CD8α T cell markers. METHODS: This was done using immunohistochemistry on a human breast cancer tissue microarray consisting of 498 consecutive cases of primary breast cancer. RESULTS: Infiltration of γδ T cells and T cell infiltration in general (CD3), correlated with a good prognosis, while Treg infiltration with a worse. Infiltration of γδ T cells was associated with a significantly improved clinical outcome in all breast cancer subtypes except triple negative tumors. Only infiltration of either CD3+ or CD8α+ cells was independently associated with better prognosis for all breast cancer patients. CONCLUSIONS: This study sheds further light on the prognostic impact of various T cell subtypes in breast cancer

Wide range of metallic and organic contaminants in various tissues of the Antarctic prion, a planktonophagous seabird from the Southern Ocean

International audienceTrace elements (n=14) and persistent organic pollutants (POPs, n=30)were measured in blood, liver, kidney, muscle and feathers of 10 Antarctic prions (Pachyptila desolata) from Kerguelen Islands, southern Indian Ocean, in order to assess their concentrations, tissue distribution, and inter-tissue and inter-contaminant relationships. Liver, kidney and feathers presented the highest burdens of arsenic, cadmium and mercury, respectively. Concentrations of cadmium, copper, iron, and zinc correlated in liver and muscle, suggesting that uptake and pathways of metabolism and storage were similar for these elements. The major POPs were 4,4’-DDE, mirex, PCB-153 and PCB-138. The concentrations and tissue distribution patterns of environmental contaminants were overall in accordance with previous results in other seabirds. Conversely, some Antarctic prions showed surprisingly high concentrations of BDE-209. This compound has been rarely observed in seabirds before, and its presence in Antarctic prions could be due to the species feeding habits or to the ingestion of plastic debris. Overall, the study shows that relatively lower trophic level seabirds (zooplankton-eaters) breeding in the remote southern Indian Ocean are exposed to a wide range of environmental contaminants, in particular cadmium, selenium and some emerging-POPs, which merits further toxicological investigations