A hallmark of leukocytes is their ability to migrate among tissues. This allows them to communicate with changing cellular partners throughout development, notify cells in the lymph nodes and spleen about infections in distant organs of and co-ordinate immune responses. In recent years, multiphoton microscopy has revolutionized our ability to track cells in live animals and gain new insights on immune function. Our laboratory is set to study diverse processes in the immune system. All of these processes have three features in common: they are highly dynamic, they depend on multicellular communication and they can only be studied in intact animals. Major focuses of the lab are CD8 T cells and dendritic cells (DCs).
Research Projects
For the immune system to gain knowledge of pathogens invading the skin, and for skin-based vaccination to work, a specialized cell, called a dendritic cell (DC) needs to migrate from the skin to lymph nodes carrying antigens it sampled from skin pathogens. The molecular and morphological changes that enable DCs to enter lymphatic vessels and reach lymph nodes are poorly defined, as they cannot be studied in a dish. Using multiphoton microscopy we want to determine whether, upon sensing inflammation in the skin, DCs start to migrate and enter small lymphatics. What is the anatomic route DCs use to enter lymphatics and what are the molecular signals involved in their interaction with the cells lining the lymphatic vessels.
For a successful immune response to a skin pathogen or cutaneous vaccination, two rare cells – a DC carrying antigen and a clonotypic T cell expressing a T cell receptor specific for the antigen – must find each other in the lymph node. We have previously showed that DCs form stable networks in the T zone and those newly immigrating DCs, injected into the skin, join these existing networks. Studies show that T cells migrate vigorously on these networks before they locate the right DCs to interact with – the one carrying the optimal amounts of antigen. Other studies show that DCs transfer antigen among themselves through various mechanisms. We hypothesize that antigen is transferred among DCs across the lymph node, allowing T cells to locate the DCs carrying most antigen and have devised ways to reconstitute DC networks in vitro as well as in vivo allowing visualization and measurements of this process in live mice.Our initial results indicate that DCs transfer antigens in vitro and in lymph nodes), and that this transfer greatly assists the activation of Naive T cells.
Recently it was described that DCs in the bone marrow define a novel niche dedicated for hosting mature B and T cells and supporting mature B cell survival. In collaboration the Jung lab, we are examining whether this structure, coined the immunological bone-marrow niche, can also support immune responses, studying the motility and activation of mature cells participating in immune responses within these niches. Our initial examination identified the baseline behavior of these cells in the bone marrow.
Melanoma patients can mount an immune response against a tumor, as evidences by T cells that can selectively kill tumor cells which proliferate and infiltrate the tumors. Although these cytotoxic T cells (CTLs) can kill melanoma cells in the dish, they usually fail to stop tumor development – partially because the tumor cells induce an immunosuppressive environment inside the tumor. We are observing the interactions between CTLs and tumor cells within B16 melanomas, following the events that allow CTLs, as a cell community, to eliminate a whole tumor. For that we have developed a method to microscopically follow the interactions between CTLs and melanoma cells inside intradermal tumors in mice. Additionally using this model we can visualize.,the mechanisms by which the immune system resist metastases to nearby lymph nodes.
The role of dendritic cells and regulatory T cells (Tregs) in inflammatory bowel disease is being studied in the lab. We have developed a method to externalize the colon to watch the behavior of leukocytes in the lamina propria of live mice