Influence of the Fibroblastic Reticular Network on Cell-Cell Interactions in Lymphoid Organs

Secondary lymphoid organs (SLO), such as lymph nodes and the spleen, display a complex micro-architecture. In the T cell zone the micro-architecture is provided by a network of fibroblastic reticular cells (FRC) and their filaments. The FRC network is thought to enhance the interaction between immune cells and their cognate antigen. However, the effect of the FRC network on cell interaction cannot be quantified to date because of limitations in immunological methodology. We use computational models to study the influence of different densities of FRC networks on the probability that two cells meet. We developed a 3D cellular automaton model to simulate cell movements and interactions along the FRC network inside lymphatic tissue. We show that the FRC network density has only a small effect on the probability of a cell to come into contact with a static or motile target. However, damage caused by a disruption of the FRC network is greatest at FRC densities corresponding to densities observed in the spleen of naïve mice. Our analysis suggests that the FRC network as a guiding structure for moving T cells has only a minor effect on the probability to find a corresponding dendritic cell. We propose alternative hypotheses by which the FRC network might influence the functionality of immune responses in a more significant way

The extracellular matrix of the spleen as a potential organizer of immune cell compartments

Until recently little information was available on the molecular details of the extracellular matrix (ECM) of secondary lymphoid tissues. There is now growing evidence that these ECMs are unique structures, combining characteristics of basement membranes and interstitial or fibrillar matrices, resulting in scaffolds that are strong and highly flexible and, in certain secondary lymphoid compartments, also forming conduit networks for rapid fluid transport. This review will address the structural characteristics of the ECM of the murine spleen and its potential role as an organizer of immune cell compartments, with reference to the lymph node where relevant

Functional and Homeostatic impact of Age-Related Changes in Lymph node Stroma

Adults over 65 years of age are more vulnerable to infectious disease and show poor responses to vaccination relative to those under 50. A complex set of age-related changes in the immune system is believed to be largely responsible for these defects. These changes, collectively termed immune senescence, encompass alterations in both the innate and adaptive immune systems, in the microenvironments where immune cells develop or reside, and in soluble factors that guide immune homeostasis and function. While age-related changes in primary lymphoid organs (bone marrow, and, in particular, the thymus, which involutes in the first third of life) have been long appreciated, changes affecting aging secondary lymphoid organs, and, in particular, aging lymph nodes (LNs) have been less well characterized. Over the last 20 years, LN stromal cells have emerged as key players in maintaining LN morphology and immune homeostasis, as well as in coordinating immune responses to pathogens. Here, we review recent progress in understanding the contributions of LN stromal cells to immune senescence. We discuss approaches to understand the mechanisms behind the decline in LN stromal cells and conclude by considering potential strategies to rejuvenate aging LN stroma to improve immune homeostasis, immune responses, and vaccine efficacy in the elderly.113Ysciescopu

Antigen-presenting cells and antigen presentation in tertiary lymphoid organs

Tertiary lymphoid organs (TLOs) form in territorialized niches of peripheral tissues characterized by the presence of antigens; however, little is known about mechanism(s) of antigen handling by ectopic lymphoid structures. In this mini review, we will discuss the role of antigen-presenting cells and mechanisms of antigen presentation in TLOs, summarizing what is currently known about this facet of the formation and function of these tissues as well as identifying questions yet to be addressed

Immune function and dysfunction are determined by lymphoid tissue efficacy

Lymphoid tissue returns to a steady state once each immune response is resolved, and although this occurs multiple times throughout life, its structural integrity and functionality remain unaffected. Stromal cells orchestrate cellular interactions within lymphoid tissue, and any changes to the microenvironment can have detrimental outcomes and drive disease. A breakdown in lymphoid tissue homeostasis can lead to a loss of tissue structure and function that can cause aberrant immune responses. This Review highlights recent advances in our understanding of lymphoid tissue function and remodelling in adaptive immunity and in disease states. We discuss the functional role of lymphoid tissue in disease progression and explore the changes to lymphoid tissue structure and function driven by infection, chronic inflammatory conditions and cancer. Understanding the role of lymphoid tissues in immune responses to a wide range of pathologies allows us to take a fuller systemic view of disease progression

Lymph Node Stromal Cell Subsets

The spatiotemporal regulation of immune responses in the lymph node (LN) depends on its sophisticated tissue architecture, consisting of several subcompartments supported by distinct fibroblastic stromal cells (FSCs). However, the intricate details of stromal structures and associated FSC subsets are not fully understood. Using several gene reporter mice, we sought to discover unrecognized stromal structures and FSCs in the LN. The four previously identified FSC subsets in the cortex are clearly distinguished by the expression pattern of reporters including PDGFRb, CCL21-ser, and CXCL12. Herein, we identified a unique FSC subset expressing both CCL21-ser and CXCL12 in the deep cortex periphery (DCP) that is characterized by preferential B cell localization. This subset was clearly different fromCXCL12highLepRhigh FSCs in themedullary cord, which harbors plasma cells. B cell localization in the DCP was controlled chiefly by CCL21-ser and, to a lesser extent, CXCL12. Moreover, the optimal development of the DCP as well as medulla requires B cells. Together, our findings suggest the presence of a unique microenvironment in the cortex-medulla boundary and offer an advanced view of the multi-layered stromal framework constructed by distinct FSC subsets in the LN

Alterations in the Composition of Lymph Node Stromal Cells Under Nutritional Challenge

Lymph nodes belong to the main actors in adaptive immunity, as they accommodate the cells of our acquired immunology, namely dendritic cells, T-cells and B-cells. Moreover they are its infrastructural and functional junction as immune cells, antigen and cytokines permanently flow through these secondary lymphatic organs. Therefore they are in need of cells which support as well as maintain the lymph node's structure and possess the ability to provide a proper immune response. This task is mainly fulfilled by so called fibroblastic reticular cells, which belong, next to lymphatic endothelial cells and blood endothelial cells, to mesenchymal stromal cells and are the main focus of research. This work focuses on how stromal cells in lymph nodes are influenced by diet. Since famine is not just an important issue in third world countries, but also in western countries, special diets and malnutrition caused by cancer are an every day epiphany. Hence it is an interesting question how diets impact the lymph node's cellular structure. We have established an experimental system to study the effect of acute starvation in secondary lymphoid organs and to follow the alterations associated with the regression phase when food is again accessible. During short-term starvation and regression phase stromal cell populations decreased in lymph nodes. This change reflected the decrease of cell populations in absolute numbers, while the proportions in the frequency of stromal subpopulations remained the same. Additionally, the regression phase was associated with decreased podoplanin expression in stromal cells, in particular in FRCs. To identify possible mechanism for the decrease in stromal cell populations, we addressed leptin-leptin receptor pathway in SLOs. Indeed, we have identified leptin receptor variants in fibroblastic reticular cells (FRCs) where Western blot analysis revealed that next to an unfunctional knock-out receptor there is also the long functional LepRb isoform expressed. Addition of leptin during starvation is suspected to partially protect cell loss in lymph nodes. Yet more details about fibroblastic reticular cells' physiology have to be revealed in future studies regarding leptin signaling in lymph nodes as well as the return to status quo after the beginning of the regression phase.Da Lymphknoten die angepasstesten Zellen des erworbenen Immunsystems beherbergen, nämlich dendritische Zellen, T-Zellen und B-Zellen, gehören sie zu den wichtigsten Schauplätzen der erworbenen Immunität. Sie sind als infrastrukturelle und funktionelle Knotenpunkte im immunologischen Geschehen zu bewerten: Antigene und Cytokine kommen ständig in Kontakt mit diesen sekundären lymphatischen Organen, daher werden spezialisierte Zellen benötigt, welche die Struktur des Lymphknotens erhalten, sowie die Befähigung besitzen, eine adäquate Immunantwort zu unterstützen. Diese Aufgabe wird vor Allem durch sogenannte fibroblastische retikuläre Zellen übernommen. Diese Zellen gehören neben lymphatischen Endothelzellen und Blutendothelzellen zu den sogenannten mesenchymalen Stromazellen. Auf sie wird in dieser Arbeit das Hauptaugenmerk gelegt, wobei der Fokus auf dem Einfluss bestimmter Ernährungszustände auf die im Lymphknoten ansässigen Stromazellen liegt. Entgegen der populären Meinung, Mangel- und Unterernährung sei nur eine Problematik die Drittweltländer betrifft, lässt sich kundtun, dass beide Formen durch spezielle Diäten oder malignomassoziierte Malnutrition auch als ein Phänomen westlicher Kulturkreise häufig angetroffen werden können. Daher ist die Klärung der Frage, inwiefern diese Ernährungsformen die Struktur von Lymphknoten auf zellulärer Ebene verändern von höchster Wichtigkeit. Wir haben einen experimentellen Aufbau entwickelt mit dem wir die Auswirkungen, die eine akute Hungerphase sowie die darauffolgende Erholungsphase bei Renutrition auf den Lymphknoten hat, erforschen konnten. Während einer kurzfristigen Hungerphase und der darauffolgenden Erholung konnte beobachtet werden, dass die Populationen der verschiedenen Stromazellen untergehen. Dies zeigte sich in dem Abfall der absoluten Zellzahlen im Lymphknoten, wohingegen die Zusammensetzung der gesamten Stromazellpopulation unaffektiert blieb. Außerdem kam es in der Erholungsphase zu einer verminderten Podoplaninexpression der Stromazellen, insbesondere in FRC. Um einen möglichen Mechanismus für den Untergang von Stromazellpopulationen aufzudecken, untersuchten wir die Leptin- Leptinrezeptor Signalkaskade in SLO. Tatsächlich konnten wir veschiedene Varianten des Leptinrezeptors auf FRC feststellen: Western Blot Analysen ergaben, dass neben einem knock-out-Rezeptor auch die lange, funktionstüchtige Isoform LepRb exprimiert wird. Die Zugabe von Leptin während der Hungerphase wird verdächtigt die Zellen im Lymphknoten teilweise vor zellulärem Untergang zu schützen. Es müssen jedoch noch weitere unklare Sachstände zu der Physiologie von FRC erörtert werden. Dazu gehört insbesondere die Signalkaskade des Leptinrezeptors und wann die Struktur des Lymphknotenstromas nach Beginn der Erholungsphase zum Status quo zurückkehrt

Association of T-Zone Reticular Networks and Conduits with Ectopic Lymphoid Tissues in Mice and Humans

Ectopic or tertiary lymphoid tissues (TLTs) are often induced at sites of chronic inflammation. They typically contain various hematopoietic cell types, high endothelial venules, and follicular dendritic cells; and are organized in lymph node–like structures. Although fibroblastic stromal cells may play a role in TLT induction and persistence, they have remained poorly defined. Herein, we report that TLTs arising during inflammation in mice and humans in a variety of tissues (eg, pancreas, kidney, liver, and salivary gland) contain stromal cell networks consisting of podoplanin+ T-zone fibroblastic reticular cells (TRCs), distinct from follicular dendritic cells. Similar to lymph nodes, TRCs were present throughout T-cell–rich areas and had dendritic cells associated with them. They expressed lymphotoxin (LT) β receptor (LTβR), produced CCL21, and formed a functional conduit system. In rat insulin promoter–CXCL13–transgenic pancreas, the maintenance of TRC networks and conduits was partially dependent on LTβR and on lymphoid tissue inducer cells expressing LTβR ligands. In conclusion, TRCs and conduits are hallmarks of secondary lymphoid organs and of well-developed TLTs, in both mice and humans, and are likely to act as important scaffold and organizer cells of the T-cell–rich zone