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, to the lymphatic vessel lumen and, subsequently, guides them into the lymph nodes. In the lymph nodes, dendritic cells present the antigens and activate pathogen-specific T cells.
Our research group focuses on two key events that are essential for efficient lymphatic function. First, we explore how sprouting lymphangiogenesis is controlled to yield a well-structured functional lymphatic vessel network. Second, we investigate how lymphatic endothelium guides dendritic cell entry into the lymphatic system via the dynamic presentation of chemokines. To address these questions, we use in vivo models, tissue explants, cell culture assays, and state-of-the-art microscopy.
We explore potential targets for the regulation 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.
Our research group is 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. Specifically, we investigate two key events of cell guidance: sprouting lymphangiogenesis and dendritic cell entry into the lymphatic system.
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, e.g. 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 the 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 lymphatic vessel networks. As an additional research focus, we investigate the early phases of lymphangiogenic sprouting of mature lymphatic vessels. We want to know the cellular and molecular mechanisms that determine the site of lymphatic endothelial sprouting, and allow lymphatic endothelial cells to escape the ordered structure of the endothelium and invade the interstitial tissue. In these studies, we use a combination of genetic and small-molecular approaches in in vivo-, tissue explant-, and cell culture models.
Lymphatic capillaries have been considered as passive conduits of tissue fluid. However, recent data supports a model where lymphatic endothelial cells actively attract antigen-presenting dendritic cells into the lymphatic capillary lumen.
We have shown that dendritic cells and lymphatic endothelium 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 determines the site of dendritic cell transmigration across the lymphatic endothelium and how dendritic cells are guided to this site. In these studies, we use primary cell cultures and tissue explant models where we can examine dendritic cell transmigration across lymphatic endothelium. A special focus is laid on the spatio-temporal presentation of lymphatic endothelial chemokines. Our main aim is the identification of molecular handles, whose manipulation would enhance the functional capacity of lymphatic capillaries for the boosting of adaptive immunity.
Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell surface expression. Korhonen E. A., Murtomäki A., Jha S.K., Anisimov A., Pink A., Zhang Y., Stritt S., Liaqat I., Stanczuk L., Alderfer L., Sun Z., Kapiainen E., Singh A., Sultan I., Lantta A., Leppänen V.M., Eklund L., He Y., Augustin H.G., Vaahtomeri K., Saharinen P., Mäkinen T., Alitalo K. 1 Aug 2022, J Clin Invest., 132(15):e155478.
Shape and function of interstitial chemokine CCL21 gradients are independent of heparan sulfates produced by lymphatic endothelium. Vaahtomeri K., Moussion C., Hauschild R., Sixt M. 25 Feb 2021, Front Immunol. 12:630002, 2021.
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.
Inam Liaqat, Doctoral student
Emma Jakobsson, Undergraduate student
Maria Saario, Undergraduate student
Ida Hilska, Undergraduate student
Emmi Tiilikainen (Technician)
Sonja Granroth (Master’s student)