Topological Small-World Organization of the Fibroblastic Reticular Cell Network Determines Lymph Node Functionality

Abstract

Fibroblastic reticular cells (FRCs) form the cellular scaffold of lymph nodes (LNs) and establish distinct microenvironmental niches to provide key molecules that drive innate and adaptive immune responses and control immune regulatory processes. Here, we have used a graph theory-based systems biology approach to determine topological properties and robustness of the LN FRC network in mice. We found that the FRC network exhibits an imprinted small-world topology that is fully regenerated within 4 wk after complete FRC ablation. Moreover, in silico perturbation analysis and in vivo validation revealed that LNs can tolerate a loss of approximately 50% of their FRCs without substantial impairment of immune cell recruitment, intranodal T cell migration, and dendritic cell-mediated activation of antiviral CD8+ T cells. Overall, our study reveals the high topological robustness of the FRC network and the critical role of the network integrity for the activation of adaptive immune responses.

Critical Issues in Modelling Lymph Node Physiology

“…These predictions warrant further experimental analysis. In addition, a more detailed analysis of our artificially generated FRC network showed that this network has a similar mean shortest path length to a random network but a much greater degree of clustering giving a large small-worldness value indicative of a small-world type network, which is qualitatively but not quantitatively matching to what was found experimentally [14]. In our study, we were interested in assessing the small-worldness property of the model network graph embedded into metric space, i.e.…”

“…The values suggest that this network has a similar mean shortest path length to a random network but a much greater degree of clustering giving a large small-worldness value indicative of a small-world type network. Analysis of actual FRC networks have shown average small-worldness values of 6.128 across 6 mice [14]. This is of particular relevance to FRC networks given their hypothesised role in maintaining chemokine gradients.…”

“…The FRC network can be severely destroyed during viral infection leading to immune deficiency [8]. It has been shown recently that an FRC network can tolerate a loss of approximately 50% of their FRCs without substantial impairment of immune cell recruitment, intranodal T cell migration, and dendritic cell-mediated activation of antiviral CD8 + T cells [14]. To evaluate the robustness of the conduit system in terms of the lymph percolation parameter, we have examined the lymph flow through the conduit network for an idealized geometry and under specified boundary conditions.…”

“…B cell follicles are located underneath the SCS where B-cell specific responses take place [10], whilst the inner LN area constitutes the T cell zone where T cells are activated through interaction with antigen-presenting cells, such as dendritic cells (DCs) [11]. Fibroblastic reticular cells (FRCs) form a densely intertwined network that supports T-DC interactions, subsequently leading to generation of immune responses [12][13][14]. Furthermore, FRCs support lymphocyte migration, retention and survival through expression of chemokines CCL19 and CCL21 [15] and survival factor IL-7 [16,17].…”

“…Viral infections suffered by the immune system can destroy parts of the FRC network and lead to its disruption [8,14]. We applied the model of lymph flow in the conduit system to parameterize the destruction process and study its effect on lymphatic system function.…”