"Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (Mtb) and currently one third of the world’s population is latently infected with Mtb, in spite of the existence of a vaccine. This scenario is in part due to Mtb’s ability to adapt to current treatments, e.g. development of multi-resistance to antibiotics. However we also lack a proper understanding of the immunological mechanisms subverted by Mtb to establish a chronic infection and the reasons for the failure of the current vaccine to provide protection. Hence, new cross-disciplinary approaches are required to identify at what level Mtb virulence factors or the current vaccine strain prevent the induction of a protective immune response.Here we will identify the mechanisms by which mycobacterium strains subvert T cell immunity that is critical for the protection from fatal infection. We will do this in the context of an infection with virulent Mtb and vaccination with the current vaccine strain (BCG) or a new attenuated Mtb strain that is a promising candidate for a new TB vaccine. To this purpose we will investigate a critical step for the initiation of T cell immunity against mycobacteria, the migration of infected dendritic cells to the draining lymph node.Our approach will make use of unique tools to gain new insights into the interaction between host factors and mycobacteria virulence factors. These include novel intravital multiphoton microscopy studies of the infectious process in the lung and cross-disciplinary approaches such as a high-throughput screen of a library of Mtb mutants for regulators of dendritic cell function.This research proposal will benefit from the unique synergy between the expertise in mycobacterium’s biology of the host institution and my immunological expertise of T cell immunity. Therefore, we foresee making significant contributions that will be instrumental for the development of new vaccines and more efficient treatments of TB."