Abstract
The splenic white pulp is underpinned by poorly characterized stromal cells that demarcate distinct immune cell microenvironments. Here we establish fibroblastic reticular cell (FRC)-specific fate-mapping in mice to define their embryonic origin and differentiation trajectories. Our data show that all reticular cell subsets descend from multipotent progenitors emerging at embryonic day 19.5 from periarterial progenitors. Commitment of FRC progenitors is concluded during the first week of postnatal life through occupation of niches along developing central arterioles. Single cell transcriptomic analysis facilitated deconvolution of FRC differentiation trajectories and indicated that perivascular reticular cells function both as adult lymphoid organizer cells and mural cell progenitors. The lymphotoxin-β receptor-independent sustenance of postnatal progenitor stemness unveils that systemic immune surveillance in the splenic white pulp is governed through subset specification of reticular cells from a multipotent periarterial progenitor cell. In sum, the finding that discrete signaling events in perivascular niches determine the differentiation trajectories of reticular cell networks explains the development of distinct microenvironmental niches in secondary and tertiary lymphoid tissues that are crucial for the induction and regulation of innate and adaptive immune processes.
Highlights
The splenic white pulp is underpinned by poorly characterized stromal cells that demarcate distinct immune cell microenvironments
Generation of functional immune environments in lymph nodes depends on maturation and functional specialization of fibroblastic reticular cells (FRC) that are associated with the broad expression of the mucin-type transmembrane protein podoplanin (PDPN)[12,13,14]
Individual cell fatemapping of E19.5 mesenchymal lymphoid tissue organizer (mLTo) cells to 6 weeks revealed that single colored EYFP+ or RFP+ cell clusters contain distinct FRC subsets with PDPN+ T-cell zone reticular cells (TRC), CD21/35+ follicular dendritic cell (FDC) or single MAdCAM1+ marginal reticular cells (MRC), which is indicative of locally proliferating progenitors (Supplementary Fig. 3f–h). These results suggest that FRC subset specification from embryonic mLTo cells occurs through clonal expansion in local microenvironments during the interaction with hematopoietic cells
Summary
The splenic white pulp is underpinned by poorly characterized stromal cells that demarcate distinct immune cell microenvironments. The first line of immune defense is provided by the marginal zone of the white pulp where microbial antigens are captured by myeloid cells[5,6] and innate immune responses are initiated[7] Both T- and B-cell compartments of the white pulp are underpinned by specialized fibroblastic stromal cells that provide a physical scaffold and generate chemokines and cytokines to facilitate efficient interaction between immune cells[8,9]. The analysis of cellular lineage relationship requires knowledge on the embryonic origin and subsequent commitment steps that determine the critical nodes in the differentiation trajectories Both red and white pulp fibroblastic stromal cells descend from stem cells in the embryonic splenopancreatic mesenchyme[2]
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