Smashing another long held belief in lymphology

Updated: Sep 6

Just when you thought the lymphatic system could not get any more fascinating and surprising, the latest research on the structural elements of the lymph nodes and their role in immune modulation is mind blowing.

Last year I reported briefly on emerging research which showed that

fibroblastic reticular cells influence the action of immune cells inside lymph nodes

The abstract of the article by Brown et al in Nature Immunology(1) is pasted at the end of this post, or read the TL post here.

A further article by Perez-Shibayama and colleagues (3) explains how FRC's - the fibre building cells that produce the reticular infrastructure of the lymph node and the spleen, are triggered by viruses, bacteria, parasites and other messenger molecules. The FRCs then influence the action of all kinds of immune cells such as B & T-cells and natural killers cells, as well as macrophages and neutrophils, with outcomes that lead to either protective immunity or immuno-pathological damage.

The authors conclude that FRC contribute to the maintenance of tissue homeostasis in all kinds of immune aggregates, and we are just scratching the surface on understanding the mechanisms. I won't pretend to understand very much of the article, but it does make my brain ping with questions about how this all relates to lymphatic dysfunction. Especially in the interaction with FRCs and fat associated lymphoid clusters (FALC) in the gut. So now the old brain is pinging about the gut microbiome, and that could lead down a whole rabbit hole of as yet, unanswerable questions. Luckily we've got lots of clever brains working on things like this!

Another recent finding removes any last barrier to rejecting the idea that lymph nodes are passive filtering stations that simply house immune cells and isolate the lymph from the surrounding tissue (2). Not only are the very walls influencing how immune interactions take place,

there are neural interactions inside the nodes, where antigen presenting cells and other immune cells are hard wired with neural filaments.

These neural filaments are found in the sub-capsular sinus and medullary cords of the lymph nodes. So while the endothelial cells are monitoring whats in the lymph and influencing lymphatic pumping or isolating the node (see the TL post on swollen lymph nodes), neural networks are keeping an eye on immune reactions, and its happening in your spleen, thymus and even under your skin.

So much for decades of asserting that only the capsule of the lymph node is innervated!

1: Brown FD, Sen DR, LaFleur MW, Godec J, Lukacs-Kornek V, Schildberg FA, et al. Fibroblastic reticular cells enhance T cell metabolism and survival via epigenetic remodeling. Nature Immunology. 2019;20(12):1668-80.

Abstract Lymph node fibroblastic reticular cells (FRCs) respond to signals from activated T cells by releasing nitric oxide, which inhibits T cell proliferation and restricts the size of the expanding T cell pool. Whether interactions with FRCs also support the function or differentiation of activated CD8+ T cells is not known. Here we report that encounters with FRCs enhanced cytokine production and remodeled chromatin accessibility in newly activated CD8+ T cells via interleukin-6. These epigenetic changes facilitated metabolic reprogramming and amplified the activity of pro-survival pathways through differential transcription factor activity. Accordingly, FRC conditioning significantly enhanced the persistence of virus-specific CD8+ T cells in vivo and augmented their differentiation into tissue-resident memory T cells. Our study demonstrates that FRCs play a role beyond restricting T cell expansion—they can also shape the fate and function of CD8+ T cells.

2: Wülfing C, Schuran FA, Urban J, Oehlmann J, Günther HS. Neural architecture in lymphoid organs: Hard-wired antigen presenting cells and neurite networks in antigen entrance areas. Immunity, Inflammation and Disease. 2018;6(2):354-70.

Introduction: Recently, we found abundant innervation ofantigen presenting cells that were reached and enclosed by single neurites. These neurally hard-wired antigen presenting cells (wAPC) could be observed in the T-cell zone ofsuperficial cervical lymph nodes of rats and other mammalians, including humans. Methods: As a consequence, we investigated lymph nodes at many different anatomical positions as well as all primary and secondary lymphoid organs (SLO) in rodents for a similar morphology of innervation regarding antigen presenting cells known in those tissues. Results: As a result, we confirmed wAPC in lymph nodes independent from their draining areas and anatomical positions but also in all other T-cell zones of lymphoid organs, like Peyer’s patches, NALT and BALT, as well as in the thymic medulla. Other cells were innervated in a similar fashion but with seemingly missing antigen presenting capacity. Both types of innervated immune cells were observed as being also present in the dermis of the skin. Only in the spleen wAPC could not be detected. Beyond this systematic finding, we also found another regular phenomenon: a dense network of neurites that stained for neurofilament always in antigen entrance areas of lymphoid organs (subsinoidal layer of lymph nodes, subepithelial dome ofPeyer’s patches, subsinoidal layer ofthe splenic white pulp, margins of NALT and BALT). Lastly, also thymic epithelial cells (TEC) restricted to the corticomedullary junction of the thymus showed similar neurofilament staining. Conclusions: Therefore, we propose much more hard-wired and probably afferent connections between lymphoid organs and the central nervous system than is hitherto known.

3: Perez-Shibayama C, Gil-Cruz C, Ludewig B. Fibroblastic reticular cells at the nexus of innate and adaptive immune responses. Immunological Reviews. 2019;289(1):31-41.

Summary Lymphoid organs guarantee productive immune cell interactions through the establishment of distinct microenvironmental niches that are built by fibroblastic reticular cells (FRC). These specialized immune-interacting fibroblasts coordinate the migration and positioning of lymphoid and myeloid cells in lymphoid organs and provide essential survival and differentiation factors during homeostasis and immune activation. In this review, we will outline the current knowledge on FRC functions in secondary lymphoid organs such as lymph nodes, spleen and Peyer's patches and will discuss how FRCs contribute to the regulation of immune processes in fat-associated lymphoid clusters. Moreover, recent evidence indicates that FRC critically impact immune regulatory processes, for example, through cytokine deprivation during immune activation or through fostering the induction of regulatory T cells. Finally, we highlight how different FRC subsets integrate innate immunological signals and molecular cues from immune cells to fulfill their function as nexus between innate and adaptive immune responses.