Maria Ulvmar – Stromal cell mediated immune regulation in the lymph node

The focus of our research is to understand the impact the highly specialized lymph node vasculature has on the structure and function of the lymph node in the regulation adaptive immune responses, particularly the immune response in cancer disease.

The lymph nodes are closely integrated with the lymphatic system, often arranged in chains along the colleting lymphatic vessels. They consist of a complex parenchyma of immune cells; arranged into distinct T-cell and B-cell areas.

The organization of immune cells within the lymph node is highly dependent on and controlled by the lymph node stroma, which includes a complex network of lymphatic sinuses, specialized blood vessels, and mesenchymal cells.

Specialized function of lymph node vessels

We and others have recently shown that the lymphatic endothelium in the lymph nodes have unique functions and expression of immune-modulatory genes that cannot be found in the lymphatic vessels of other organs (Ulvmar MH, Nat. Immunol. 2014). This specialization and heterogeneity of the lymph node vasculature has earlier been unknown.

Our data supports that growing peripheral tumours and metastatic tumour cells, affect the expression of these genes and thereby affects immune regulation. We therefore think it is important to broaden the focus on stromal cells in cancer to also include the lymph node stromal cells in order to understand the mechanisms behind immune evasion in cancer disease.

Lymph nodes are involved in tumour metastasis

Metastatic dissemination to lymph nodes is common and can in some tumour types, e.g. malignant melanoma and breast cancer, be a separate prognostic indicator, associated with increased risk for further metastatic dissemination in the body and disease recurrence after surgical removal of the primary tumour.

Increased knowledge about regulation of immune response

Our work is divided in two parts:

  1. We want to understand more both about the general specialization of the vasculature in the lymph node and how it contributes to immune regulation in homoeostasis.
  2. We want to investigate how cancer-induced changes of the lymph node stroma affect the immune response in cancer and cancer cells' ability to spread further in the body (metastasize).

Cell sorting and gene analysis

Our lab is specialized in advanced flow cytometry and cell sorting for stromal cell analysis where we combine traditional antibody labelling with novel fluorescent reporter genes to sort rare subsets of endothelial cells with high specificity. This is combined with confocal imaging to spatially map different types of vessels, analyse changes in protein expression and to understand the interactions between vessels, immune cells and cancer cells.

We also use advanced model systems, where we can genetically target and delete genes specifically endothelial cells. Our experimental studies are complemented with studies of human tumour draining lymph nodes to identify genes that can be of clinical relevance for human cancer treatment.
 

You can find further information about Maria Ulvmar’s research on http://www.molps.se/scholars/

The lymp node structure.
a) Whole mount projection and optical slice of adult mouse sciatic lymph node. All lymphatic endothelial cells (LECs) are labelled by a EGFP reporter. The lymphatic marker Lyve-1 displays distinct parts of the lymph node lymphatic vasculature including the medullary sinuses.
b) Cryo section of adult mouse inguinal lymph node. CCL21 is expressed by the lymph node high endothelial venules (HEVs) and the fibroblastic reticular cells (FRCs). Langerin is expressed by migratory dendritic cells (DCs). Lyve-1 displays part of lymphatic networkm. Scale bars 250 mm. (unpublished data Ulvmar MH)