Ontogeny and functional characterization of splenic fibroblastic reticular cells (FRCs) and their mesenchymal precursors during homeostasis, immune-activation and infection
Final Report Abstract
During this collaborative work we establish an FRC-specific fate mapping in mice to define their embryonic origin and differentiation trajectories. We found that all reticular cell subsets descend from pluripotent progenitors that emerge at embryonic day 19.5 from Sca-1+ periarterial progenitors. Commitment of FRC progenitors was 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 revealed that perivascular reticular cells function both as adult lymphoid organizer cells and as mural cell progenitors. Finally, the LTβR-independent sustenance of postnatal progenitor stemness unveiled that a systemic immune surveillance in the splenic white pulp is regulated through subset specification of reticular cells from a pluripotent periarterial progenitor cell. In conclusion, the concept that discrete signaling levels in perivascular niches determine the nature of reticular cell networks provides a theoretical framework for further exploration of immune processes in secondary and tertiary lymphoid tissues. A direct functional role of FRCs in innate immune reactions could not be confirmed in several experimental model systems eg. LPS-induced-inflammation, cical ligation and puncture (CLP) and DSS-induced colitis, using our genetic model of CCL19-specific ablation of LTβR expression (CLL19-Cre x LTβRflox/flox mice). However, testing these mice in an experimental model of adaptive immune activation by using an allogenic skin transplantation model we observed a prolong allograft survival in the CCL19-Cre x LTβRflox/flox mice. Furthermore, expression array analysis identified several pro-inflammatory mediators induced in FRCs upon immune activation. Especially the induction of inducible nitric oxide synthase (iNOS), known to have suppressive function on T cell activation, gave reason to generate a new mouse model in which iNOS is expressed in CCL19-expressing cells (CCL19-tTA x TetO-iNOS). Interestingly, these mice are characterized by a prolonged transplant survival in an allogeneic skin transplant model system. Further analysis revealed that pro-inflammatory cytokines seem to important for the induction of iNOS in CCL19-expressing cells. In summary, our results indicate a functional role of FRC-derived mediators in modulating adaptive immune responses.
Publications
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Lymphatic endothelial cells control initiation of Lymph Node Organogenesis. Immunity 2017; 47: 80
Onder L, Mörbe U, Pikor N, Novkovic M, Cheng HW, Hehlgans T, Pfeffer K, Becher B, Waisman A, Rülicke T, Gommerman J, Müller CG, Sawa S, Scandella E, Ludewig B
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Origin and differentiation trajectories of fibroblast reticular cells in the splenic white pulp. Nat. Commun. 2019; 10:1739
Cheng H-W, Onder L, Novkovic M, Soneson C, Lutge M, Pikor N, Scandella E, Robinson MD, Miyazaki J, Tersteegen A, Sorg U, Pfeffer K, Rülicke T, Hehlgans T and Ludewig B
