The lymphatic system is essential for the induction of adaptive immune responses in a variety of conditions with associated inflammation, such as cardiovascular and neurological diseases and tumorigenesis. Lymphatic vessels transport dendritic cells that present pathogen-derived antigens in the lymph nodes, where they activate T-lymphocytes. These target the pathogens for destruction. In addition to the trafficking of the dendritic cells, the lymphatic system enables resolution of the inflammatory conditions by draining the inflammation-associated tissue debris. Accordingly, lymphatic vessels have been considered as a promising target for regulation of adaptive immunity in inflammation-associated diseases.
Our objective is to identify mechanisms that regulate lymphatic function, for example, the drainage of excess fluid that has leaked out of blood vessels and dendritic cell transport. To this end, our research focuses on the process of sprouting lymphangiogenesis and the dendritic cell entry into the lymphatic system, respectively. To address these questions, we use in vivo models, tissue explants, cell culture assays, and state-of-the-art microscopy.
We explore the potential of the identified targets in regulating the level of adaptive immunity in in vivo models. These studies should form a basis for strategies to treat patients suffering from diseases in which inflammation is an essential component.
Molecular mechanisms of sprouting lymphangiogenesis
Lymphatic vessels form dense tree-like networks in various organs. The tree-top is formed by blind-ended lymphatic capillaries, which are sites of immune cell and tissue fluid entry. Although most of the capillaries are generated during development, lymphatic capillaries can also grow in length and caliber in adult tissues in various conditions associated with inflammation.
The density of the lymphatic capillaries correlates with the efficiency of tissue fluid drainage and inflammation resolution. Accordingly, experimentally induced lymphangiogenesis leads to enhanced T-cell activation and enhances adaptive immunity. Thus, tools to enhance controlled lymphangiogenic sprouting, elongation, and subsequent maturation should allow enhanced adaptive immune responses.
We explore various opportunities to expand the lymphatic capillary networks in a controlled manner. We also focus on characterization of the lymphatic capillary network architecture and its developmental mechanisms using a holistic approach, including experimental and computational approaches (in collaboration with Dr. Edouard Hannezo, IST Austria). These studies aim to identify overall principles governing the formation of the lymphatic vessel networks.
As an additional research focus, we investigate the early phases of lymphangiogenic sprouting. We want to know the cellular and molecular mechanisms that allow lymphatic endothelial cells to detach from the endothelium in a mature lymphatic capillary and to sprout to the adjacent tissue. In these studies, we use a combination of genetic and small-molecular approaches in in vivo-, tissue explant-, and cell culture models.
Lymphatic endothelial guidance of dendritic cell entry into the lymphatic system
Lymphatic capillaries have been considered as passive conduits for tissue fluid. However, recent data supports a model were lymphatic endothelial cells actively attract antigen-presenting dendritic cells into the lymphatic capillary lumen.
We have shown that dendritic cells and lymphatic endothelia engage in a paracrine cross-talk before dendritic cell transmigration across the lymphatic endothelium. Approaching dendritic cells push the lymphatic endothelium, resulting in “on-demand” secretion of lymphatic endothelial chemokine CCL21, which provides a positive feedback loop further urging dendritic cells to enter the lymphatic capillary.
In our current research, we address the question of what the lymphatic endothelial transmigration cues are, and how they are controlled in space and time. In these studies, we use primary cell cultures (Figure 2) and tissue explant models where we can examine dendritic cell transmigration across lymphatic endothelium.
To summarize our research, we aim at the identification of molecular handles, whose manipulation would enhance the functional capacity of lymphatic capillaries for the boosting of the adaptive immunity.
Locally triggered release of chemokine CCL21 promotes dendritic cell transmigration across lymphatic endothelia. Vaahtomeri K, Brown M, Hauschild R, De Vries I, Leithner AF, Mehling M, Kaufmann WA, Sixt M. 2 May 2017, Cell Reports, 19(5):902-909.
CCL21 promotes tissue egress of intralymphatic dendritic cells through afferent lymphatic vessels. Russo E.*, Teijeira A.*, Vaahtomeri K., Wilbrodt, AH., Bloch, JS., Nitschke, M., Santambrogio, L., Kerjaschki, D., Sixt, M., Halin, C.”, 23 February 2016, Cell Reports, 14(7):1723-1734.
Dendritic cells interpret Haptotactic Chemokine Gradients in a manner governed by signal-to-noise ratio and dependent on GRK6. Schwarz J, Bierbaum V, Vaahtomeri K, Hauschild R, Brown M, de Vries I, Leithner A, Reversat A, Merrin J, Tarrant T, Bollenbach T, Sixt M. 8 May 2017, Current Biology, 27(9):1314-1325.
Lymphatic exosomes promote dendritic cell migration along guidance cues. Brown M, Johnson LA, Leone DA, Majek P, Vaahtomeri K, Senfter D, Bukosza N, Schachner H, Asfour G, Langer B, Hauschild R, Parapatics K, Hong YK, Bennett KL, Kain R, Detmar M, Sixt M, Jackson DG, Kerjaschki D. 4 June 2018, Journal of cell biology, 217(6):2205-2221.
Lymphangiogenesis guidance by paracrine and pericellular factors. Vaahtomeri K., Karaman S., Mäkinen T., Alitalo K., 15 August 2017, Genes & Development, 31(16):1615-1634. 27(9):1314-1325.
Lymphatic vessels in tumor dissemination versus immunotherapy. Vaahtomeri , K., Alitalo, K. September 2020, Cancer Research, 80:3463–5.
Emmi Tiilikainen, Technician
Inam Liaqat, Doctoral student
Ida Hilska, Under graduate student
Sonja Granroth, Master’s student