Ontogeny and functional characterization of splenic fibroblastic reticular cells (FRCs) and their mesenchymal precursors during homeostasis, immune-activation and infection

点击翻译按钮获取中文摘要

Secondary lymphatic organs (SLOs) such as the spleen provide specialized microenvironmental niches for the development and control of immune responses. Particular mesenchymal stromal cells known as fibroblastic reticular cells (FRCs) generate distinct compartments that permit, for example, highly efficient interaction of T cells with dendritic cells. Importantly, FRCs are more than simple scaffold-building cells; these cells actively participate in inducing and shaping innate and adaptive immune responses. Our own preliminary data demonstrate that the structure and function of the splenic white pulp exclusively depends on lymphotoxin-beta-receptor (LTbR) signaling received by CCL19 positive FRCs during adult life and/or their putative progenitors, i.e. mesenchymal lymphoid tissue organizer cells (mLTOs). In continuation of our existing collaborative activities, we have developed a novel inducible lineage tracing model that permits genetic tagging of splenic FRCs and their progenitors in vivo and will thus facilitate the elucidation of their differentiation pathways throughout spleen development. In addition, this model system provides means for the identification and characterization of molecular mechanisms involved in the maintenance of splenic structure and immune-competence during adult life. Thus, in combination with our already established experimental model of cell type-specific loss of LTbR function, we will be able to resolve the temporal requirement of LTbR signaling for differentiation and function of adult splenic FRCs and their putative progenitors in the embryo. Finally, using an experimental model that facilitates cell type specific re-activation of LTbR expression in a timely controlled manner, we will test the hypothesis whether FRC-restricted LTbR expression within a specific time window is sufficient for proper white pulp formation and function during embryonic life. Furthermore, we will elucidate the requirements for a timely controlled LTbR activation during adult life in order to maintain compartmentalization and function of the splenic white pulp. Our proposed objectives are based on our individual expertise and present the continuation of our successful collaborative activities. More specifically, they are designed to molecularly characterize splenic FRCs and to dissect lineage relationship of splenic FRCs with other splenic stromal cells, e.g. their differentiation from mLTO precursors during embryonic development. Moreover, we will be able to identify and functionally characterize the cellular and molecular mechanisms through which LTbR expressing FRCs are involved in the maintenance of lymphoid organ integrity and immune-competence in the adult spleen, i.e. their ecological role in the splenic micro-environment during immune homeostasis, activation and infection.