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.