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.
Highlights
Efficient interactions between the immune system and microbial antigens are initiated and maintained in secondary lymphoid organs (SLOs) that are strategically positioned at routes of pathogen invasion
By utilizing high-resolution microscopy coupled with computational approaches to complex network analysis, we determined the topological properties and robustness of the fibroblastic reticular cell (FRC) network
The underlying structure of the FRC network has been identified as a small-world network analogous to many other biological networks
Summary
Efficient interactions between the immune system and microbial antigens are initiated and maintained in secondary lymphoid organs (SLOs) that are strategically positioned at routes of pathogen invasion. The interaction of naïve T cells with antigen-presenting dendritic cells (DCs) in LNs needs to be well coordinated because T cells with a particular specificity are rare [2,3]. Optimal communication between immune cells relies to a large extent on the fibroblastic reticular cell (FRC) network that provides specialized microenvironments for cellular interactions. FRCs regulate T cell migration and survival in the T cell zone by producing homeostatic chemokines and cytokines [4,5,6]. While the role of FRCs in the regulation of immune responsiveness has been studied extensively (reviewed in [10,11]), the underlying principles of the FRC network topology and its contribution to general LN functionality have remained unexplored
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