Reina Mebius More on research
Functional development of the immune system
The generation of an immune response is dependent on efficient interaction of rare antigen-specific T cells with dendritic cells that present the antigen. The likelihood that these two infrequent cells encounter each other is greatly enhanced by the existence of lymph nodes which are organized to mediate efficient interaction of these cell subsets. Thus, lymph nodes are viewed as professional immune response factories. Moreover, they are formed during embryogenesis as a direct result of the interaction between stromal organizer cells and hematopoietic inducer cells. This leads to the production of chemokines and adhesion molecules by organizer cells, attracting more hematopoietic cells. Within inflammatory lesions that are characteristic of autoimmune disease, a similar interaction of organizer and inducer cells can be envisioned. Stromal fibroblasts can be viewed as organizer cells, which upon continuous triggering by activated lymphocytes, produce factors that recruit and retain other cells. This may lead to the formation of tertiary lymphoid structures, found in inflammatory lesions of autoimmune patients, which at times show a similar organization as seen in lymph nodes. It is likely that in the case of autoimmune diseases, a high degree of organization will worsen the disease since efficient presentation of autoantigens will enhance activation of autoreactive T cells. However, these structures have also been reported to develop in response to a persistent pathogen, and in this case they may in fact facilitate the process of pathogen elimination.
We are delineating the cellular and molecular mechanisms that mediate the differentiation of stromal cells towards organizing cells, allowing the attraction of hematopoietic cells to the developing lymph nodes. In addition, the subsequent differentiation of these cells into the different stromal cell subsets that are present within lymph nodes are studied. Furthermore, similar processes are examined during the development of tertiary lymphoid structures in chronic inflammatory diseases.
Within adult lymph nodes these stromal cells differentiate into reticular fibroblasts that enwrap the reticular fibers, which allow rapid transport of molecules such as antigens, chemokines, and cytokines to the inner part of the lymphoid organs. Many dendritic cells are covering these reticular fibroblasts and their interaction can be seen as an anchoring within the lymphoid tissues until they pick up antigen from the conduit that needs to be presented or receive stimulatory signals that mediate their maturation. One can envision that interaction of dendritic cells with stromal fibroblasts as not merely a means of attachment, but that reticular fibroblasts also provide cues to these dendritic cells for their functioning as antigen presenting cells. In addition, stromal cells have been shown to be able to act as antigen presenting cells themselves. We are addressing the role of stromal cells as antigen presenting cells, as well as their influence on the antigen presenting function of dendritic cells.