| The research in the Mebius lab is focused on the development of the immune system, with emphasis on the formation of lymph nodes. Within adult secondary and tertiary lymphoid tissues, we study how the lymphoid stromal microenvironment supports the maintenance of immune tolerance and chronic inflammation, respectively. Within our group a unique cell population, identified by expression of CD45, CD4 and lack of CD3 and TCR (CD45+CD4+CD3- cells), was identified to be abundantly present in developing lymph nodes. These cells are responsible for inducing lymph node formation, by virtue of their ability to express lymphotoxin. Furthermore, these CD45+CD4+CD3- cells are absent in ROR[gamma]-/- and strongly reduced in TRANCE-/- mice, coinciding with the absence of lymph nodes. To support the hypothesis that CD45+CD4+CD3- cells are inducing lymph node development, LN formation could be rescued by restoring the number of CD45+CD4+CD3- cells in TRANCE-/- mice. Subsequently, it was shown that CD45+CD4+CD3- cells also induce Peyer s patches and Nasal Associated Lymphoid Tissue. Therefore, CD45+CD4+CD3- cells are now indeed believed to be the true lymphoid tissue inducer cells (Lti cells). Cells that receive signals from inducer cells are the organizer cells, which are stromal cells that express the LT[bèta]R. Upon triggering of the LT[bèta]R, chemokines and adhesion molecules are induced, which subsequently attract and retain cells that constitute the lymph node anlage. By adoptive transfer of these cells we have shown that these stromal organizers have the capacity to attract and to organize host derived lymphocytes. This interaction with lymphocytes results in further differentiation of stromal cells to fibroblastic reticular cells (FRC) of the T cell area and follicular dendritic cells (FDC) of the B cell follicles. The FRC are part of a specialized structure of reticular fibers and extracelluar components, the reticular network (RN). This network functions as a conduit system that directs rapid transport of molecules such as antigens, chemokines and cytokines to the inner part of the lymphoid organs. Furthermore, this network functions as a scaffold for interactions between immune cells. FRCs that are associated with the RN are in contact with DCs. Their interaction can be thought of as an anchoring of DC within the lymphoid tissues allowing them to pick up antigen from the conduit and to present this to T cells. And thus, FRCs provide a microenvironment for the efficient induction of immune responses. In addition, they might very well further influence the behaviour of immune cells. Similarly, FDCs in the B cell follicles provide a framework for B cells to move along and a platform for B cells to recognize antibody-antigen complexes, allowing survival of the B cells with highest affinity of their BCR for the antigen. Using intravital 2-photon microscopy, antigen transport to the FDC can be followed, allowing real time imaging of immune processes within the B cell follicle. |
