Immunological Synapse

International audienceImmunological synapses are dynamically organised cell–cell interfaces formed between cells of the immune system. Different types of immunological synapses lead to distinct functional outcomes. Thus, T and B lymphocytes form immunological synapses with each other and with dendritic cells or macrophages, conveying mutual activation cues. Moreover, natural killer cells or cytotoxic T lymphocytes form synapses with tumour or infected cells delivering cytotoxic granules that destroy those anomalous cells. Immunological synapses are the result of an orchestrated cell polarisation process that involves cytoskeleton rearrangements, intracellular vesicle traffic and the clustering of receptors, adhesion molecules and signalling effectors, which together ensure the immunological synapse stability, its structure and function. Immunological synapses play key roles in immune responses, like T- and B-cell activation, and polarised secretion of cytokines or cytotoxic granules

Rac1-Rab11-FIP3 regulatory hub coordinates vesicle traffic with actin remodeling and T-cell activation

International audienceThe immunological synapse generation and function is the result of a T-cell polarization process that depends on the orchestrated action of the actin and microtubule cytoskeleton and of intracellu-lar vesicle traffic. However, how these events are coordinated is ill defined. Since Rab and Rho families of GTPases control intracellu-lar vesicle traffic and cytoskeleton reorganization, respectively, we investigated their possible interplay. We show here that a significant fraction of Rac1 is associated with Rab11-positive recycling endosomes. Moreover, the Rab11 effector FIP3 controls Rac1 intra-cellular localization and Rac1 targeting to the immunological synapse. FIP3 regulates, in a Rac1-dependent manner, key morphological events, like T-cell spreading and synapse symmetry. Finally, Rab11-/FIP3-mediated regulation is necessary for T-cell activation leading to cytokine production. Therefore, Rac1 endosomal traffic is key to regulate T-cell activation

Adenomatous Polyposis Coli Defines Treg Differentiation and Anti-inflammatory Function through Microtubule-Mediated NFAT Localization

International audienceAdenomatous polyposis coli (APC) is a polarity regulator and tumor suppressor associated with familial adenomatous polyposis and colorectal cancer development. Although extensively studied in epithelial transformation, the effect of APC on T lymphocyte activation remains poorly defined. We found that APC ensures T cell receptor-triggered activation through Nuclear Factor of Activated T cells (NFAT), since APC is necessary for NFAT’s nuclear localization in a microtubule-dependent fashion and for NFAT-driven transcription leading to cytokine gene expression. Interestingly, NFAT forms clusters juxtaposed with microtubules. Ultimately, mouse Apc deficiency reduces the presence of NFAT in the nucleus of intestinal regulatory T cells (Tregs) and impairs Treg differentiation and the acquisition of a suppressive phenotype, which is characterized by the production of the anti-inflammatory cytokine IL-10. These findings suggest a dual role for APC mutations in colorectal cancer development, where mutations drive the initiation of epithelial neoplasms and also reduce Treg-mediated suppression of the detrimental inflammation that enhances cancer growth

Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion

International audienceWhile mutations leading to a compromised nuclear envelope cause diseases such as muscular dystrophies or accelerated aging, the consequences of mechanically induced nuclear envelope ruptures are less known. Here we show that nuclear envelope ruptures induce DNA damage which promotes senescence in non-transformed cells, and induces an invasive phenotype in human breast cancer cells. We find that the ER-associated exonuclease TREX1 translocates into the nucleus after nuclear envelope rupture and is required to induce DNA damage. Inside the mammary duct, cellular crowding leads to nuclear envelope ruptures which generate TREX1-dependent DNA damage, thereby driving the progression of in situ carcinoma to the invasive stage. DNA damage and nuclear envelope rupture markers were also enriched at the invasive edge of human tumors. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells