Epithelia provide the first line of defense of the immune system. Epithelial cells express patterns of recognition receptors that detect environmental stimuli, secrete endogenous danger signals and pave the way for immune cells arrival with chemokines, adhesion, and extra cellular matrix molecules. Furthermore, during chronicle infection/inflammation, remodeling of lymphatic and blood microvasculature allows tissue to favor traffic of leukocytes between lymph nodes and inflamed tissues. We follow 4 axis to tackle complementary aspects of immune response.
In thematic 4, the remodeling of pulmonary tissue, epithelium and endothelium will be studied in the case of severe asthma in humans and whopping cough infection with mice models. The extravasation of leukocytes from the blood stream to inflamed tissue is achieved by a sequence of rolling on-, crawling on-, and transmigration events through- the endothelium under the action of blood flow and chemical signals expressed by endothelial cells. In lymph nodes, the intense traffic of T cells and antigen presenting cells (APCs) in a confined environment is precisely orchestrated by poorly characterized chemicals signals to segregate cells in their respective follicles and favor the encounter with agonist cells.
In thematic 3, the mechanic and chemotactic signaling involved in blood extravasation and lymph node trafficking will be investigated in controlled microfluidic assays in vitro, and in pulmonary infection/inflammation models in vivo. Arrest of immune cell in vasculature as well as T cell/APC recognition in lymph node involve tightly regulated and accurate molecular interactions at the membrane of cells and adaptive signaling that filter/amplify relevant information.
In thematic 2, the physics of cell adhesion and T cell activation will be studied as a function of the physiological physical constraints (membrane fluctuations, ligand mobility, force on molecular links,…). Finally, all cellular phenotypes and decisions described above depend on specific protein/protein recognition, whose kinetics is not well understood due to the multiplicity of recognition configurations and to the inherent difficulty to probe molecular interactions experimentally.
In thematic 1, the kinetic and force dependence of T cell receptor/HLA and antigen/antibody recognition will be studied in physiologically relevant planar geometry, and then applied to therapeutic antibody selection.