Potent antitumour activity of interleukin-2-Fc fusion proteins requires Fc-mediated depletion of regulatory T-cells

Interleukin-2 (IL-2) is an established therapeutic agent used for cancer immunotherapy. Since treatment efficacy is mediated by CD8 + and NK cell activity at the tumour site, considerable efforts have focused on generating variants that expand these subsets systemically, as exemplified by IL-2/antibody complexes and 'superkines'. Here we describe a novel determinant of antitumour activity using fusion proteins consisting of IL-2 and the antibody fragment crystallizable (Fc) region. Generation of long-lived IL-2-Fc variants in which CD25 binding is abolished through mutation effectively prevents unwanted activation of CD25 + regulatory T-cells (Tregs) and results in strong expansion of CD25 - cytotoxic subsets. Surprisingly, however, such variants are less effective than wild-type IL-2-Fc in mediating tumour rejection. Instead, we report that efficacy is crucially dependent on depletion of Tregs through Fc-mediated immune effector functions. Our results underpin an unexpected mechanism of action and provide important guidance for the development of next generation IL-2 therapeutics

Cytosolic Recognition of RNA Drives the Immune Response to Heterologous Erythrocytes

The archetypal T cell-dependent antigen is sheep red blood cells (SRBCs), which have defined much of what we know about humoral immunity. Early studies using solubilized or sonicated SRBCs argued that the intact structure of SRBCs was important for optimal antibody responses. However, the reason for the requirement of intact SRBCs for the response to polyvalent protein antigen remained unknown. Here, we report that the immune response to SRBCs is driven by cytosolic recognition of SRBC RNA through the RIG-I-like receptor (RLR)-mitochondrial anti-viral signaling adaptor (MAVS) pathway. Following the uptake of SRBCs by antigen-presenting cells, the MAVS signaling complex governs the differentiation of both T follicular cells and antibody-producing B cells. Importantly, the involvement of the RLR-MAVS pathway precedes that of endosomal Toll-like receptor pathways, yet both are required for optimal effect. Immunization with sheep red blood cells (SRBCs) has been used for almost a century to study antibody generation. Loetsch et al. now show that, after engulfment, SRBC RNA accesses antigen-presenting cell RNA-sensing pathways to stimulate the immune system

Combination of M-Estimators and Neural Network Model to Analyze Inside/Outside Bark Tree Diameters

Part 1: ANN-Classification and Pattern RecognitionInternational audienceOne of the most important statistical tools is linear regression analysis for many fields such as medical sciences, social sciences, econometrics and more. Regression techniques are commonly used for modelling the relationship between response variables and explanatory variables. In this study, inside bark tree diameter was used as the dependent variable and outside bark diameter and site type as independents. While generally it is assumed that inside and outside bark diameters are linearly correlated, linear regression application is weak in the presence of outliers. The purpose of this study was to develop a Multi-Layer Perceptron neural network model which considered significant variables from an a priori developed robust regression model. The application of robust regression could be considered in selecting the input variables in a neural network model

Effects of field plot configurations on the uncertainties of ALS-assisted forest resource estimates

The effects of field plot configurations on the uncertainties of plot-level forest resource estimates were analyzed using airborne laser scanner data, aerial photographs and field measurements. The aim was to select a field sample plot configuration that can be used for both large area and management inventories. Error estimates were evaluated at the plot level using six different training plot configurations. Additionally, separate plots with two different sizes were used for evaluation. Stem volume and five other forest resource characteristics were considered. The field measurement costs of the different plot configurations were also studied. RMSEs and mean deviations for airborne laser scanning ALS-assisted estimates were practically the same for the fixed radius plot, the two concentric plots and the angle count plot with a basal area factor of q = 1 for all three evaluation plot sizes. Angle count plots with basal area factors of q = 1.5 and 2 increased the RMSEs. For the former plot configurations, the RMSEs for the ALS-assisted estimates could be attributed to inaccuracy in the predicted relationships between the field data and ALS data, not to the training plot configuration. Tree measurements and costs can, therefore, be reduced from those of the Finnish management inventories without increasing RMSEs.201

The retroelement Lx9 puts a brake on the immune response to virus infection

The notion that mobile units of nucleic acid known as transposable elements can operate as genomic controlling elements was put forward over six decades ago. However, it was not until the advancement of genomic sequencing technologies that the abundance and repertoire of transposable elements were revealed, and they are now known to constitute up to two-thirds of mammalian genomes3,4 . The presence of DNA regulatory regions including promoters, enhancers and transcription-factor-binding sites within transposable elements5–8 has led to the hypothesis that transposable elements have been co-opted to regulate mammalian gene expression and cell phenotype8–14. Mammalian transposable elements include recent acquisitions and ancient transposable elements that have been maintained in the genome over evolutionary time. The presence of ancient conserved transposable elements correlates positively with the likelihood of a regulatory function, but functional validation remains an essential step to identify transposable element insertions that have a positive effect on fitness. Here we show that CRISPR–Cas9- mediated deletion of a transposable element—namely the LINE-1 retrotransposon Lx9c11—in mice results in an exaggerated and lethal immune response to virus infection. Lx9c11 is critical for the neogenesis of a non-coding RNA (Lx9c11-RegoS) that regulates genes of the Schlafen family, reduces the hyperinflammatory phenotype and rescues lethality in virus-infected Lx9c11−/− mice. These findings provide evidence that a transposable element can control the immune system to favour host survival during virus infection.Nenad Bartonicek, Romain Rouet, Joanna Warren, Claudia Loetsch, Gabriela Santos Rodriguez, Stacey Walters, Francis Lin, David Zahra, James Blackburn, Jillian M. Hammond, Andre L. M. Reis, Ira W. Deveson, Nathan Zammit, Mahdi Zeraati, Shane Grey, Daniel Christ, John S. Mattick, Tatyana Chtanova, Robert Brink, Marcel E. Dinger, Robert J. Weatheritt, Jonathan Sprent, Cecile Kin