Mechanisms underlying unconventional T cell function as decision points to prevent microbial spread via the lymph
Prof. Dr. Wolfgang Kastenmüller
Following the breach of epithelial barriers and local infections in tissues, the innate immune system is activated and initiates a cascade of events with the aim to re-establish and enforce the barrier and to eliminate invading pathogens. However, some pathogens are difficult to control, replicate quickly and have means to disseminate through and between tissues. A typical route of dissemination is the lymphatic system, facilitated by the open funnel-like structure of lymphatic vessels. Therefore, lymph nodes (LNs) play an important role as immunological filters that fight infections and prevent the spread of microbes into the blood stream. We have previously shown that unconventional T cells (UTC) are strategically positioned in the lymph node to fight incoming infections. They secrete effector cytokines like IL17 or IFN-γ, which are molecular decision points that determine bacterial spreading. In our preliminary work, we found that tissue-derived UTC continously migrate via the lymphatic route to locally draining LNs. Because each tissue harbours a distinct spectrum of UTC with locally adapted differentiation states and distinct T-cell receptor (TCR) repertoires, every draining LN is populated by a distinctive tissue-determined mix of such lymphocytes. Therefore, we hypothesise that LNs which drain distinct tissues have a different capacity to limit bacterial spreading of specific classes of pathogens and that this is based on the function and LN-characteristic composition of UTC. Our data further show that UTC are organised within functional units with a remarkable level of redundancy. Therefore, we will apply novel genetic approaches to target all UTC instead of single TCR-based UTC lineages (NKT - natural killer T cells, MAIT – mucosal associated invariant T cells and γδ T cells) to unravel their function as a population. We hope that this project will provide novel angles for host directed therapies against microbial dissemination.