We are intrigued by one of the most complex biological events: how migrating cells reach their destination, i.e., how cell migration guidance cues are generated and interpreted. To investigate this fundamental question, we use lymphatics and the associated immune cells as a model system and have established a research platform, which combines a multitude of microscopy approaches and innovative cell migration models. To complement our strengths we collaborate with scientists, whose expertise ranges from immunology to biophysics. The chosen approach allows a multi-scale view of complex biological systems, such as lymphatics.
Significance and rationale: Adaptive immune response is a key effector in a variety of common diseases, which are of huge physical, mental, and economic burden. For example, adaptive immunity is essential to fight pathogen invasion, vaccine-induced immunity, and destruction of tumor cells, and, it also, affects the outcome of heart and coronary diseases. On the other hand, exacerbated adaptive immune responses are causative of autoimmune diseases and transplant rejections.
Recent years have revolutionized our understanding of the role of the lymphatic system in the control of adaptive immunity. To start an adaptive immune response, lymphatic vessel endothelium actively recruits antigen-presenting dendritic cells, first, to the lymphatic vessel lumen and, subsequently, traffics them into the lymph nodes. In the lymph nodes, dendritic cells present the antigens and, thus, activate T cells, which, in turn, target the pathogens. The level of adaptive immunity correlates with the number of antigen-presenting dendritic cells homing to lymph nodes. We aim to identify molecular handles that could be used for boosting adaptive immunity.
Research interests:
Immune cell guidance cues: While working with Prof. Michael Sixt (IST Austria), Kari showed that dendritic cells trigger the on-demand release of lymphatic endothelial CCL21, resulting in high concentration CCL21 depots that guide dendritic cell entry, i.e., transmigration, into the lumen of lymphatic capillaries (Vaahtomeri et al., 2017, Cell reports; Vaahtomeri et al., 2021, Front. Immunol.). Now we investigate how the spatio-temporal presentation of chemokines guides the leukocytes to the preferred site of transmigration.
Mechanisms of controlled lymphatic capillary network expansion: Lymphatic vessel networks expand upon inflammation, resulting in increased lymphatic capacity and, thus, adaptive immune response. In our second line of investigation, we investigate the mechanisms that allow efficient tissue coverage by lymphatic vessel networks. These studies have revealed a novel mechanism of developmental lymphatic network expansion: lymphatic endothelium senses the local density of the lymphatic network, resulting in sprouting at low-density regions, self-correction of the gaps in the network, and, thus, optimal tissue coverage (Ucar et al., Nature Communications 2023). Based on these results, the Vaahtomeri group now investigates the factors that limit/allow the sprouting of mature lymphatic vessels in adults.
Altogether, the multi-scale approach of the Vaahtomeri research group will culminate in the identification of molecular mechanisms that could be used for unleashing the sprouting potential of the lymphatic endothelium in a controlled manner, resulting in increased capacity to recruit and traffic dendritic cells into the lymph nodes.