Efficiently stimulated adult microglia cross‐prime naive CD8+ T cells injected in the brain

Microglia are the major myeloid‐immune cells of the brain parenchyma. In a steady state, microglia monitor their environment for pathogens or damaged cells. In response to neural injury or inflammation, microglia become competent APCs able to prime CD4⁺ and CD8⁺ T lymphocytes. We previously demonstrated that neonatal and adult microglia cross‐present exogenous soluble Ags in vitro. However, whether microglia are able to cross‐present Ag to naive CD8⁺ T cells in vivo, within the brain microenvironment, remains undetermined. Here, we have designed an original protocol in order to exclude the involvement in cross‐presentation activity of peripheral migrating APCs and of CNS‐associated APCs. In C57Bl/6 mice, in which the body but not the head has been properly irradiated, we analyzed the ability of resident microglia to stimulate intracerebrally injected CD8⁺ T cells in vivo. This study demonstrates for the first time that adult microglia cross‐present Ag to naive CD8⁺ T cells in vivo and that full microglia activation is required to overcome the inhibitory constrains of the brain and to render microglia able to cross‐prime naive CD8⁺ T cells injected in the brain. These observations offer new insights in brain‐tumor immunotherapy based on the induction of cytotoxic antitumoral T cells.     

CRIPTO overexpression promotes mesenchymal differentiation in prostate carcinoma cells through parallel regulation of AKT and FGFR activities

Members of the EGF-CFC (Cripto, FRL-1, Cryptic) protein family are increasingly recognized as key mediators of cell movement and cell differentiation during vertebrate embryogenesis. The founding member of this protein family, CRIPTO, is overexpressed in various human carcinomas. Yet, the biological role of CRIPTO in this setting remains unclear. Here, we find CRIPTO expression as especially high in a subgroup of primary prostate carcinomas with poorer outcome, wherein resides cancer cell clones with mesenchymal traits. Experimental studies in PCa models showed that one notable function of CRIPTO expression in prostate carcinoma cells may be to augment PI3K/AKT and FGFR1 signaling, which promotes epithelial-mesenchymal transition and sustains a mesenchymal state. In the observed signaling events, FGFR1 appears to function parallel to AKT, and the two pathways act cooperatively to enhance migratory, invasive and transformation properties specifically in the CRIPTO overexpressing cells. Collectively, these findings suggest a novel molecular network, involving CRIPTO, AKT, and FGFR signaling, in favor of the emergence of mesenchymal-like cancer cells during the development of aggressive prostate tumors.     

Time course of neuro-mechanical changes underlying stretch-shortening cycle during intermittent exhaustive rebound exercise

This study analysed the time course of neuro-mechanical changes underlying stretch?Cshortening cycle during intermittent exhaustive rebound exercise. On a sledge apparatus, ten subjects repeated until exhaustion a series of 30 unilateral submaximal rebounds, with intermediate 3-min rest periods. Rebound height, ground reaction force, 3D tibial acceleration and electromyographic activity of major lower limb muscles were recorded. A maximal drop jump test performed before and after the exhaustive exercise revealed a 10% drop in maximal stretch?Cshortening cycle (SSC) performance. Specific investigation of the neuro-mechanical changes along the exhaustive exercise included classical comparison of the first (BEG) and last (END) rebound series. From the initial accommodation phase, an optimized (OPTIM) series was individually determined as the first of at least two subsequent series with significantly shorter contact time than in the BEG series. The OPTIM series was reached after 3?±?1 series, with associated increased lower limb stiffness during the braking phase and decreased muscle activities during the push-off. The major result was that the early (BEG?COPTIM) changes explained most of the BEG?CEND ones whereas the actual (OPTIM?CEND) fatigue effects remained quite limited. This confirmed our expectation that erroneous quantification of the SSC fatigue effects might be drawn when using the early beginning of rebound exercise on the sledge as a reference. Actual fatigue effects included medio-lateral instability as suggested by increased peroneus longus preactivation and medio-lateral tibial acceleration. The present methodology is thus considered as improving the distinction between SSC optimization and its deterioration with fatigue.