We are intrigued by one of the most complex biological events: how dynamic cell-cell interactions are guided. To investigate this fundamental question, we utilize lymphatics and the associated immune cells as a model system and have established a research platform that combines a multitude of microscopy approaches with innovative in vivo, explant, and primary cell co-culture 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 and tumorigenesis and to launch vaccine-induced immunity. On the other hand, exacerbated adaptive immune responses are causative of autoimmune diseases and transplant rejections. We aim to identify the key molecules involved in lymphatic endothelial immunomodulation and immune cell trafficking for the benefit of future translational studies.
Research interests
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. On the other hand, lymphatic endothelium can directly affect T cell activity via antigen presentation. We aim to identify the key molecules involved in these functions to allow, in longer term, therapeutic manipulation of lymphatic endothelial immunomodulatory activity.
Immune cell guidance cues: Lymphatic endothelium expresses a variety of chemokines and cytokines that are sensed by the cognate receptors on the immune cells. Chemokine CCL21 is the major lymphatic endothelial guidance cue that drives the lymph node homing of peripheral CCR7-expressing dendritic cells. CCL21 mediates the entry/transmigration of dendritic cells into the lymphatic vessel lumen. We have shown that the targeted exocytosis of CCL21, at least in part, determines the preferential transmigration site on the lymphatic endothelium (Liaqat et al. 2024, The EMBO J). Interestingly, lymphatic endothelial CCL21 localizes to two distinct storage vesicle populations: the Golgi-derived RAB6+ vesicles and the RAB27+ dense core secretory granules (Liaqat et al. 2024, The EMBO J). We envision that these two secretory routes, in synergy with diffusion limiting factors at lymphatic vessel basement membrane, control lymphatic endothelial guidance cue presentation and, thus, lymphatic endothelium-immune cell interaction in space and time contributing to orchestration of adaptive immunity (Vaahtomeri et al. 2017, Cell Reports; Vaahtomeri et al. 2021, Frontiers in Immunology; Liaqat et al. 2024, The EMBO J).
Multi-scale mechanisms of controlled lymphatic capillary network expansion: Mature 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, yet controlled, lymphatic vessel tissue coverage. 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, we now investigate the factors that limit/allow the sprouting of mature lymphatic vessels in adults. Altogether, we expect that our multi-scale approach will culminate in the identification of molecular mechanisms that allow tuning of the lymphatic capacity and adaptive immunity.