Peyer's patch; Lymph node; development; fibroblastic reticular cells
Cheng Hung-Wei, Onder Lucas, Novkovic Mario, Soneson Charlotte, Lütge Mechthild, Pikor Natalia, Scandella Elke, Robinson Mark D., Miyazaki Jun-ichi, Tersteegen Anne, Sorg Ursula, Pfeffer Klaus, Rülicke Thomas, Hehlgans Thomas, Ludewig Burkhard (2019), Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp, in Nature Communications
, 10(1), 1739-1739.
Perez‐Shibayama Christian, Gil‐Cruz Cristina, Ludewig Burkhard (2019), Fibroblastic reticular cells at the nexus of innate and adaptive immune responses, in Immunological Reviews
, 289(1), 31-41.
Perez-Shibayama Christian, Gil-Cruz Cristina, Cheng Hung-Wei, Onder Lucas, Printz Andrea, Mörbe Urs, Novkovic Mario, Li Conglei, Lopez-Macias Constantino, Buechler Matthew B., Turley Shannon J., Mack Matthias, Soneson Charlotte, Robinson Mark D., Scandella Elke, Gommerman Jennifer, Ludewig Burkhard (2018), Fibroblastic reticular cells initiate immune responses in visceral adipose tissues and secure peritoneal immunity, in Science Immunology
, 3(26), eaar4539-eaar4539.
Secondary lymphoid organs such as lymph nodes (LNs) and Peyer’s patches (PPs) sample antigens from the body’s inner and outer surfaces and mediate optimal interaction of immune cells. These functions rely on the presence of specialized microenvironments that are built and maintained by fibroblastic reticular cells (FRCs). In addition to their scaffold-building function, FRCs impact on inducing and shaping innate and adaptive immune responses. However, we do not know the embryonic origin of these important cells and the molecular mechanisms underlying FRC differentiation in LNs or PPs. Our laboratory has generated the appropriate lineage-tracing and fate-mapping approach to address these questions. Accordingly, the work program of this project has been designed on the basis of two main hypotheses: (i) LN and PP FRCs originate from an organ-specific pluripotent embryonic precursor cell, and (ii) committed embryonic LN FRC progenitors descend from fat pad fibroblasts.We have generated an inducible Ccl19-iEYFP fate-mapping model that permits in vivo fate mapping of both LN and PP FRCs. Utilizing this novel tool, we will clarify whether LN FRC diversity is programmed in embryonic precursors. Next, we will assess to which extent critical molecular pathways such as lymphotoxin-beta receptor (LTbR) or alternative NF-kappaB signaling impact FRC subtype diversification. In order to determine clonal expansion and differentiation pattern during FRC subtype specification, a stochastic multicolor Cre-reporter strain will be utilized. Finally, we will provide a molecular systems biology analysis of FRC development and subtype differentiation using RNA expression analysis (RNAseq) from defined cell cohorts. Since the nature of PP FRCs is still unexplored, we will first categorize PP FRC subsets and define transgene activity in developing and adult PPs. Next, we will dissect in detail how LTbR and alternative NF-kappaB signaling govern the differentiation of PP FRC subsets. Moreover, we aim to resolve the relationship between PP FRC progenitors in the PP anlage and their contribution to the formation of PP FRC subsets in the adult.Only in recent years, has the importance of secondary lymphoid organ stromal cells for induction and regulation of immune responsiveness been appreciated. The field is now rapidly moving forward exploring functions and exploiting the potential of these cells as therapeutic targets in autoimmune diseases, cancer and infection. We anticipate that defining the origin of fibroblastic stromal cells and elaborating the mechanisms that govern subset differentiation in LNs and PPs will provide critical knowledge to further elaborate diagnostic and therapeutic avenues for various diseases.