Communication, construction, and fluid control: lymphoid organ fibroblastic reticular cell and conduit networks
Authors: Sophie E. Acton, Lucas Onder, Mario Novkovic, Victor G. Martinez, Burkhard Ludewig
Journal: Trends in Immunology (2021)

FRCs use polarized microtubule networks to direct the secretion of ECM components and construct the mammalian conduit network.The conduit network functions as a filter that monitors fluid draining peripheral tissues, and as an export system for the systemic dissemination of locally produced molecules including antibodies.Emerging evidence indicates that there are mechanosensitive mechanisms that control fluid flow through secondary lymphoid organs, and that are important for tissue homeostasis and immune function.Fluid flow through conduit systems is robust, and the conduit network remains functional throughout the perturbation of lymph node expansion in response to immunogenic challenges. Fibroblastic reticular cells (FRCs) are a crucial part of the stromal cell infrastructure of secondary lymphoid organs (SLOs). Lymphoid organ fibroblasts form specialized niches for immune cell interactions and thereby govern lymphocyte activation and differentiation. Moreover, FRCs produce and ensheath a network of extracellular matrix (ECM) microfibers called the conduit system. FRC-generated conduits contribute to fluid and immune cell control by funneling fluids containing antigens and inflammatory mediators through the SLOs. We review recent progress in FRC biology that has advanced our understanding of immune cell functions and interactions. We discuss the intricate relationships between the cellular FRC and the fibrillar conduit networks, which together form the basis for efficient communication between immune cells and the tissues they survey. Fibroblastic reticular cells (FRCs) are a crucial part of the stromal cell infrastructure of secondary lymphoid organs (SLOs). Lymphoid organ fibroblasts form specialized niches for immune cell interactions and thereby govern lymphocyte activation and differentiation. Moreover, FRCs produce and ensheath a network of extracellular matrix (ECM) microfibers called the conduit system. FRC-generated conduits contribute to fluid and immune cell control by funneling fluids containing antigens and inflammatory mediators through the SLOs. We review recent progress in FRC biology that has advanced our understanding of immune cell functions and interactions. We discuss the intricate relationships between the cellular FRC and the fibrillar conduit networks, which together form the basis for efficient communication between immune cells and the tissues they survey. The fundamental problem of communication is that of reproducing at one point either exactly or approximately a message selected at another point. … The significant aspect is that the actual message is one selected from a set of possible messages. The system must be designed to operate for each possible selection, not just the one which will actually be chosen since this is unknown at the time of design (C.E. Shannon [1.Shannon C.E. A mathematical theory of communication.Bell System Tech. J. 2021; 27: 379-423Crossref Scopus (19817) Google Scholar]). The coordinated interactions of different immune cell populations facilitate the recognition of pathogens or cancer cells to precisely orchestrate the balance between immune activation and regulation. The establishment and maintenance of this balance relies on efficient and accurate transmission of information from inner and outer body surfaces and the communication of this information between diverse immune cell populations. According to Shannon's work on the transmission of radio signals in the 1940s [1.Shannon C.E. A mathematical theory of communication.Bell System Tech. J. 2021; 27: 379-423Crossref Scopus (19817) Google Scholar], a data communication system is composed of three elements: a source of data, a communication channel, and a receiver. The fundamental problem of 'communication' – as expressed by Shannon – is for the receiver to be able to identify what data were generated by the source, based on the signal received through the channel. At a conceptual level (and paraphrasing Shannon's concept), 'information' can be defined as the resolution of uncertainty. In other words, the analogous loss of data in information transmission systems, also known as Shannon entropy, requires dedicated means and protocols to secure optimal communication. The immune system has – at least partially – resolved the uncertainty in processes underlying the activation and regulation of innate and adaptive immune cells through the establishment of dedicated hubs for immune cell interactions. In this review we highlight recent findings on how the cellular system of lymphoid organ fibroblast and non-cellular extracellular matrix (ECM; see Glossary) networks combine to facilitate the transfer of information from tissues and body surfaces to secondary lymphoid organs (SLOs). Moreover, we discuss the current state-of-the-art fibroblastic stromal cell research and how the understanding of lymphoid organ fibroblast and ECM networks can help to further elucidate the essential rules underlying communication and engagement in the mammalian immune system. SLOs, namely the splenic white pulp, lymph nodes (LNs), and Peyer's patches, are permanent structures that are generated during embryonic or postnatal development and are present throughout the mammalian body [2.Onder L. Ludewig B. A fresh view on LN organogenesis.Trends Immunol. 2018; 39: 775-787Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. The basic design principles underlying SLO tissue architecture facilitate the coordinated interaction of immune cells in dedicated microenvironments such as an antigen-sampling zone, adjacent B cell follicles, a T cell zone, and an immune cell egress zone (Figure 1A , Key figure). Immune cells can congregate in SLOs because they possess specific blood vascular entry channels, which appear, in LNs and Peyer's patches, as specialized postcapillary venules termed high endothelial venules (HEVs) [3.Ager A. High endothelial venules and other blood vessels: critical regulators of lymphoid organ development and function.Front. Immunol. 2017; 8: 45Crossref PubMed Scopus (60) Google Scholar]. Immune cells recirculating through the tissues can also access SLOs via the antigen-sampling zone, as shown for activated T and B cells entering the LN via the subcapsular sinus [4.Thomas S.N. et al.Implications of lymphatic transport to LNs in immunity and immunotherapy.Annu. Rev. Biomed. Eng. 2016; 18: 207-233Crossref PubMed Scopus (0) Google Scholar], or the splenic white pulp via the marginal sinus [5.Lewis S.M. et al.Structure and function of the immune system in the spleen.Sci. Immunol. 2019; 4eaau6085Crossref PubMed Scopus (0) Google Scholar]. Crucial immune cell interactions occur in spatially defined niches such as the priming of naïve T cells by dendritic cells in the T cell zone [6.Krishnamurty A.T. Turley S.J. LN stromal cells: cartographers of the immune system.Nat. Immunol. 2020; 21: 369-380Crossref PubMed Scopus (0) Google Scholar], the instruction of B cells by helper T (Th) cells at the T–B cell zone border, and the affinity maturation of antibodies during the germinal center reaction in the B cell zone [7.Pikor N.B. et al.Development and immunological function of LN stromal cells.J. Immunol. 2021; 206: 257-263Crossref PubMed Scopus (0) Google Scholar]. Thus, the processing of immunologically relevant information received from tissues and outer body surfaces, and communication among immune cells, are ensured in different SLOs through standard processes in functionally equivalent environments. A further principal function of SLOs is to act as a molecular filter and immunological screening system for extracellular fluids, exemplified by LNs, which form an integral part of the lymphatic system to maintain fluid homeostasis throughout the body [8.Moore J.E. Bertram C.D. Lymphatic system flows.Annu. Rev. Fluid Mech. 2018; 50: 459-482Crossref PubMed Scopus (73) Google Scholar]. The extracellular liquid generated in all body tissues is collected in initial lymphatic vessels that contain primary flap valves, which permit the collection of interstitial fluid while simultaneously preventing the intralymphatic fluid from leaking out [9.Ikomi F. et al.Interstitial fluid, plasma protein, colloid, and leukocyte uptake into initial lymphatics.J. 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Moreover, intestinal immune processes are initiated, sustained, and regulated in gut-associated lymphoid tissues, which include the Peyer's patches in the small intestine [13.Reboldi A. Cyster J.G. Peyer's patches: organizing B-cell responses at the intestinal frontier.Immunol. Rev. 2016; 271: 230-245Crossref PubMed Scopus (115) Google Scholar]. Immune cells congregated in Peyer's patches are covered by a single-cell layer of epithelial cells and have direct access to antigens and immunomodulatory substances derived from various bacteria, viruses, and fungi in intestinal fluids to stimulate the production of vast amounts of protective immunoglobulin IgA [13.Reboldi A. Cyster J.G. Peyer's patches: organizing B-cell responses at the intestinal frontier.Immunol. Rev. 2016; 271: 230-245Crossref PubMed Scopus (115) Google Scholar]. Antigen-containing fluid is funneled directly from the intestinal lumen into the subepithelial dome region of the Peyer's patch by specialized microfold (M) epithelial cells, thereby facilitating direct activation of B cells [14.Komban R.J. et al.Activated Peyer's patch B cells sample antigen directly from M cells in the subepithelial dome.Nat. Commun. 2019; 10: 2423-15Crossref Scopus (10) Google Scholar] and continuous liquid flow into the Peyer's patch parenchyma [15.Chang J.E. et al.Mechanosensing by Peyer's patch stroma regulates lymphocyte migration and mucosal antibody responses.Nat. Immunol. 2019; 20: 1506-1516Crossref PubMed Scopus (0) Google Scholar]. Extraction and processing of immunologically relevant information from the systemic circulation is coordinated in the splenic white pulp [5.Lewis S.M. et al.Structure and function of the immune system in the spleen.Sci. Immunol. 2019; 4eaau6085Crossref PubMed Scopus (0) Google Scholar]. Furthermore, blood-borne antigens released via ramifications of central arterioles into the marginal sinus are transferred to the white pulp by marginal zone B cells and macrophages [5.Lewis S.M. et al.Structure and function of the immune system in the spleen.Sci. Immunol. 2019; 4eaau6085Crossref PubMed Scopus (0) Google Scholar]. The marginal zone, which segregates the red and white pulp in mice and rats, functions as an antigen-sampling zone and is inhabited by CD169+ metallophilic macrophages [16.Martinez-Pomares L. Gordon S. CD169+ macrophages at the crossroads of antigen presentation.Trends Immunol. 2012; 33: 66-70Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar]. Similar myeloid cell subsets line the subcapsular sinuses in LNs or reside in the subepithelial dome of Peyer's patches [17.Iwasaki A. Kelsall B.L. 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Lymphocyte trafficking between the splenic white and red pulp is regulated in bridging channels, which provide avenues for naïve lymphocyte entry into the white pulp [21.Chauveau A. et al.Visualization of T cell migration in the spleen reveals a network of perivascular pathways that guide entry into T zones.Immunity. 2020; 52: 794-807Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]. In addition, the accumulation and distribution of B cells in the white pulp depends on the presence of the endothelial plasmalemma vesicle-associated protein (PLVAP) [22.Elgueta R. et al.Endothelial plasmalemma vesicle-associated protein regulates the homeostasis of splenic immature B cells and B-1 B cells.J. Immunol. 2016; 197: 3970-3981Crossref PubMed Scopus (7) Google Scholar] – a molecule that forms endothelial diaphragms and regulates liquid homeostasis through the control of serum protein leakage [23.Stan R.V. et al.The diaphragms of fenestrated endothelia: gatekeepers of vascular permeability and blood composition.Dev. Cell. 2012; 23: 1203-1218Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar], as shown by the reduction of IgM+ B cells in the spleens of mice lacking endothelial expression of PLVAP (PlvapECKO−Tie2) relative to wild-type mice [22.Elgueta R. et al.Endothelial plasmalemma vesicle-associated protein regulates the homeostasis of splenic immature B cells and B-1 B cells.J. Immunol. 2016; 197: 3970-3981Crossref PubMed Scopus (7) Google Scholar]. Likewise, lymphatic endothelial PVLAP expression controls the entry of lymphocytes and soluble antigens into the LN parenchyma, as evidenced by lymphocyte immigration to popliteal LNs (pLNs), which was almost threefold higher in PLVAP KO mice (Plvap−/−) compared with wild-type mice [24.Rantakari P. et al.The endothelial protein PLVAP in lymphatics controls the entry of lymphocytes and antigens into LNs.Nat. Immunol. 2015; 16: 386-396Crossref PubMed Scopus (0) Google Scholar]. Thus, communication between SLOs, and the activation of immune cells within SLOs, are closely linked to the regulated flow of liquids through different functional compartments. The structural scaffold of the distinct microenvironmental niches that harbor different sets of innate and adaptive immune cell populations is formed by specialized lymphoid organ fibroblasts, referred to as fibroblastic reticular cells (FRCs) [6.Krishnamurty A.T. Turley S.J. LN stromal cells: cartographers of the immune system.Nat. Immunol. 2020; 21: 369-380Crossref PubMed Scopus (0) Google Scholar,7.Pikor N.B. et al.Development and immunological function of LN stromal cells.J. Immunol. 2021; 206: 257-263Crossref PubMed Scopus (0) Google Scholar,25.Fletcher A.L. et al.The fibroblastic T cell niche in lymphoid tissues.Curr. Opin. Immunol. 2020; 64: 110-116Crossref PubMed Scopus (7) Google Scholar] (Figure 1B). FRCs generate ECM proteins that are uniquely arranged to form a fibrillary mesh known as the conduit network [26.Gretz J.E. et al.Cords, channels, corridors and conduits: critical architectural elements facilitating cell interactions in the LN cortex.Immunol. Rev. 2005; 156: 11-24Crossref Scopus (326) Google Scholar,27.Novkovic M. et al.Topological structure and robustness of the LN Conduit system.Cell Rep. 2020; 30: 893-904Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. FRCs exhibit apicobasal polarity [28.Martinez V.G. et al.Fibroblastic reticular cells control conduit matrix deposition during LN expansion.Cell Rep. 2019; 29: 2810-2822Abstract Full Text Full Text PDF PubMed Google Scholar] and completely ensheath the conduits. Original tracer studies in rat LNs determined that the conduit system filters and channels liquids from the antigen-sampling zone towards the venous vasculature and the immune cell egress zone (Figure 1B) [29.Anderson A.O. Anderson N.D. Studies on the structure and permeability of the microvasculature in normal rat LNs.Am. J. Pathol. 1975; 80: 387-418PubMed Google Scholar]. Thus, FRCs and FRC-generated conduit networks are at the nexus of immune cell communication and fluid control in SLOs. Distinct FRC subsets underpin the microenvironmental niches of SLOs to control immune cell positioning and to provide niche factors such as IL-7 [30.Link A. et al.Fibroblastic reticular cells in LNs regulate the homeostasis of naive T cells.Nat. Immunol. 2007; 8: 1255-1265Crossref PubMed Scopus (0) Google Scholar] and BAFF [31.Cremasco V. et al.B cell homeostasis and follicle confines are governed by fibroblastic reticular cells.Nat. Immunol. 2014; 15: 973-981Crossref PubMed Scopus (155) Google Scholar] for immune cell maintenance and differentiation [32.Rodda L.B. et al.Single-cell RNA sequencing of LN stromal cells reveals niche-associated heterogeneity.Immunity. 2018; 48: 1014-1028Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. FRC subsets across all SLOs can be grouped according to the immune cells they interact with and their anatomical location (Figure 1B). For instance, marginal reticular cells (MRCs) underpin the antigen-sampling zone, follicular dendritic cells (FDCs) build the germinal center, T–B border reticular cells (TBRCs) form the communication zone of Th and B cells, T cell zone reticular cells (TRCs) facilitate DC–T cell interactions, and perivascular reticular cells (PRCs) connect the FRC network to the blood vascular system [32.Rodda L.B. et al.Single-cell RNA sequencing of LN stromal cells reveals niche-associated heterogeneity.Immunity. 2018; 48: 1014-1028Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. The development and molecular definition of FRC subsets, as well as their interaction with immune cells, have been recently discussed [6.Krishnamurty A.T. Turley S.J. LN stromal cells: cartographers of the immune system.Nat. Immunol. 2020; 21: 369-380Crossref PubMed Scopus (0) Google Scholar,7.Pikor N.B. et al.Development and immunological function of LN stromal cells.J. Immunol. 2021; 206: 257-263Crossref PubMed Scopus (0) Google Scholar,25.Fletcher A.L. et al.The fibroblastic T cell niche in lymphoid tissues.Curr. Opin. Immunol. 2020; 64: 110-116Crossref PubMed Scopus (7) Google Scholar] and are briefly summarized (see Figure I in Box 1). However, what is universal to every FRC subset is the ability of classical fibroblasts to generate and organize the ECM [32.Rodda L.B. et al.Single-cell RNA sequencing of LN stromal cells reveals niche-associated heterogeneity.Immunity. 2018; 48: 1014-1028Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,33.Malhotra D. et al.Transcriptional profiling of stroma from inflamed and resting LNs defines immunological hallmarks.Nat. Immunol. 2012; 13: 499-510Crossref PubMed Scopus (0) Google Scholar]. We focus here on ECM generation, the construction and maintenance of the conduit network, and how the FRC-generated conduit network contributes to liquid flow through the SLO parenchyma, as well as how it impacts on immune cell communication under homeostatic conditions and inflammation.Box 1Paradigmatic FRC subsets as defined by single-cell transcriptomicsThe term reticular cells was first used in 1968 when a network of thin filamentous processes traversing the B cell follicle of the LN [98.Nossal G.J. et al.Antigens in immunity. XV. Ultrastructural features of antigen capture in primary and secondary lymphoid follicles.J. Exp. Med. 1968; 127: 277-290Crossref PubMed Google Scholar] and the spleen [99.Hanna M.G. Szakal A.K. Localization of 125I-labeled antigen in germinal centers of mouse spleen: histologic and ultrastructural autoradiographic studies of the secondary immune reaction.J. Immunol. 1968; 101: 949-962PubMed Google Scholar] was described. Fibroblasts showing these particular topological properties were also found in Peyer's patches [100.Nicander L. et al.Ontogeny of reticular cells in the ileal Peyer's patch of sheep and goats.Am. J. Anat. 1991; 191: 237-249Crossref PubMed Google Scholar]. The most common description for FRCs is still based on the expression of podoplanin (PDPN) and absence of the endothelial marker CD31 [30.Link A. et al.Fibroblastic reticular cells in LNs regulate the homeostasis of naive T cells.Nat. Immunol. 2007; 8: 1255-1265Crossref PubMed Scopus (0) Google Scholar]. Genetic targeting of FRCs in mouse models, for example, based on their signature chemokine expression (Ccl19–cre) [101.Chai Q. et al.Maturation of LN fibroblastic reticular cells from myofibroblastic precursors is critical for antiviral immunity.Immunity. 2013; 38: 1013-1024Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,102.Onder L. et al.Lymphatic endothelial cells control initiation of LN organogenesis.Immunity. 2017; 47: 80-92Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], permits the elaboration of the developmental origin, differentiation dynamics, and immunological functions of FRCs in vivo. In addition, single-cell transcriptomic analyses have provided high-resolution maps of FRC heterogeneity and differentiation trajectories [32.Rodda L.B. et al.Single-cell RNA sequencing of LN stromal cells reveals niche-associated heterogeneity.Immunity. 2018; 48: 1014-1028Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,91.Cheng H.-W. et al.Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp.Nat. Commun. 2019; 10: 1739Crossref PubMed Scopus (24) Google Scholar,92.Prados A. et al.Fibroblastic reticular cell lineage convergence in Peyer's patches governs intestinal immunity.Nat. Immunol. 2021; 22: 510-519Crossref PubMed Scopus (2) Google Scholar,103.Perez-Shibayama C. et al.Type I interferon signaling in fibroblastic reticular cells prevents exhaustive activation of antiviral CD8+ T cells.Sci. Immunol. 2020; 5eabb7066Crossref PubMed Google Scholar, 104.Pezoldt J. et al.Neonatally imprinted stromal cell subsets induce tolerogenic dendritic cells in mesenteric LNs.Nat. Commun. 2018; 9: 3903-3914Crossref PubMed Scopus (0) Google Scholar, 105.Pikor N.B. et al.Remodeling of light and dark zone follicular dendritic cells governs germinal center responses.Nat. Immunol. 2020; 21: 649-659Crossref PubMed Scopus (24) Google Scholar, 106.Kapoor V.N. et al.Gremlin 1+ fibroblastic niche maintains dendritic cell homeostasis in lymphoid tissues.Nat. Immunol. 2021; 22: 571-585Crossref PubMed Scopus (5) Google Scholar] (Figure IA). The major FRC subsets can be assigned to distinct niches within SLOs that correspond to the antigen-sampling regions (MRCs), B cell follicles and germinal centers (FDCs), T–B borders (TBRCs), T cell zones (TRCs), and the perivascular space (PRC). The LN medulla, an anatomical compartment that is unique for this SLO, harbors an additional, largely perivascular FRC subset termed medullary reticular cells (MedRCs) [103.Perez-Shibayama C. et al.Type I interferon signaling in fibroblastic reticular cells prevents exhaustive activation of antiviral CD8+ T cells.Sci. Immunol. 2020; 5eabb7066Crossref PubMed Google Scholar,107.Huang H.-Y. et al.Identification of a new subset of LN stromal cells involved in regulating plasma cell homeostasis.PNAS. 2018; 115: E6826-E6835Crossref PubMed Scopus (0) Google Scholar]. FRC subsets across all SLOs exhibit partially overlapping gene signatures and chemokine gradients that reflect the particular properties of the different microenvironmental niches (Figure IB). MRCs in the antigen-sampling regions express high amounts of Madcam1, Tnfsf11 (encoding RANKL), and Cxcl13, whereas FDCs are equipped with complement and Fc receptors to capture and present immune complexes to B cells, for example Cr2 and Fcer2a. TBRCs express low amounts of Cxcl13, Cxcl12, Ccl19, and Ccl21a, whereas TRCs maintain the highest expression of Ccl19, Ccl21a, and Il7 [32.Rodda L.B. et al.Single-cell RNA sequencing of LN stromal cells reveals niche-associated heterogeneity.Immunity. 2018; 48: 1014-1028Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. PRCs surrounding blood vessels express Cd34, Ly6a, and Pdgfrb – markers that have been associated with stemness and precursor potential [91.Cheng H.-W. et al.Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp.Nat. Commun. 2019; 10: 1739Crossref PubMed Scopus (24) Google Scholar,93.Krautler N.J. et al.Follicular dendritic cells emerge from ubiquitous perivascular precursors.Cell. 2012; 150: 194-206Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar]. The genes encoding ECM proteins forming conduits, for example Col1a1, Col4a1, and Dcn, are expressed by all FRC subsets [32.Rodda L.B. et al.Single-cell RNA sequencing of LN stromal cells reveals niche-associated heterogeneity.Immunity. 2018; 48: 1014-1028Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Thus, FRCs underpin immune cell communication in SLOs by elaborating migration pathways, providing growth and differentiation factors to immune cells in specific niches, and regulating flow and antigen display [6.Krishnamurty A.T. Turley S.J. LN stromal cells: cartographers of the immune system.Nat. Immunol. 2020; 21: 369-380Crossref PubMed Scopus (0) Google Scholar]. The term reticular cells was first used in 1968 when a network of thin filamentous processes traversing the B cell follicle of the LN [98.Nossal G.J. et al.Antigens in immunity. XV. Ultrastructural features of antigen capture in primary and secondary lymphoid follicles.J. Exp. Med. 1968; 127: 277-290Crossref PubMed Google Scholar] and the spleen [99.Hanna M.G. Szakal A.K. Localization of 125I-labeled antigen in germinal centers of mouse spleen: histologic and ultrastructural autoradiographic studies of the secondary immune reaction.J. Immunol. 1968; 101: 949-962PubMed Google Scholar] was described. Fibroblasts showing these particular topological properties were also found in Peyer's patches [100.Nicander L. et al.Ontogeny of reticular cells in the ileal Peyer's patch of sheep and goats.Am. J. Anat. 1991; 191: 237-249Crossref PubMed Google Scholar]. The most common description for FRCs is still based on the expression of podoplanin (PDPN) and absence of the endothelial marker CD31 [30.Link A. et al.Fibroblastic reticular cells in LNs regulate the homeostasis of naive T cells.Nat. Immunol. 2007; 8: 1255-1265Crossref PubMed Scopus (0) Google Scholar]. Genetic targeting of FRCs in mouse models, for example, based on their signature chemokine expression (Ccl19–cre) [101.Chai Q. et al.Maturation of LN fibroblastic reticular cells from myofibroblastic precursors is critical for antiviral immunity.Immunity. 2013; 38: 1013-1024Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,102.Onder L. et al.Lymphatic endothelial cells control initiation of LN organogenesis.Immunity. 2017; 47: 80-92Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], permits the elaboration of the developmental origin, differentiation dynamics, and immunological functions of FRCs in vivo. In addition, single-cell transcriptomic analyses have provided high-resolution maps of FRC heterogeneity and differentiation trajectories [32.Rodda L.B. et al.Single-cell RNA sequencing of LN stromal cells reveals niche-associated heterogeneity.Immunity. 2018; 48: 1014-1028Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,91.Cheng H.-W. et al.Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp.Nat. Commun. 2019; 10: 1739Crossref PubMed Scopus (24) Google Scholar,92.Prados A. et al.Fibroblastic reticular cell lineage convergence in Peyer's patches governs intestinal immunity.Nat. Immunol. 2021; 22: 510-519Crossref PubMed Scopus (2) Google Scholar,103.Perez-Shibayama C. et al.Type I interferon signaling in fibroblastic reticular cells prevents exhaustive activation of antiviral CD8+ T cells.Sci. Immunol. 2020; 5eabb7066Crossref PubMed Google Scholar, 104.Pezoldt J. et al.Neonatally imprinted stromal cell subsets induce tolerogenic dendritic cells in mesenteric LNs.Nat. Commun. 2018; 9: 3903-3914Crossref PubMed Scopus (0) Google Scholar, 105.Pikor N.B. et al.Remodeling of light and dark zone follicular dendritic cells governs germinal center responses.Nat. Immunol. 2020; 21: 649-659Crossref PubMed Scopus (24) Google Scholar, 106.Kapoor V.N. et al.Gremlin 1+ fibroblastic niche maintains dendritic cell homeostasis in lymphoid tissues.Nat. Immunol. 2021; 22: 571-585Crossref PubMed Scopus (5) Google Scholar] (Figure IA). The major FRC subsets can be assigned to distinct niches within SLOs that correspond to the antigen-sampling regions (MRCs), B cell follicles and germinal centers (FDCs), T–B borders (TBRCs), T cell zones (TRCs), and the perivascular space (PRC). The LN medulla, an anatomical compartment that is unique for this SLO, harbors an additional, largely perivascular FRC subset termed medullary reticular cells (MedRCs) [103.Perez-Shibayama C. et al.Type I interferon signaling in fibroblastic reticular cells prevents exhaustive activation of antiviral CD8+ T cells.Sci. Immunol. 2020; 5eabb7066Crossref PubMed Google Scholar,107.Huang H.-Y. et al.Identification of a new subset of LN stromal cells involved in regula