Communication, construction, and fluid control: lymphoid organ fibroblastic reticular cell and conduit networks

Abstract

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. FRCgenerated 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. Coordinating communication for immune responsesThe 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]).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], 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 Shannonis 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 hasat least partiallyresolved 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 Highlights FRCs use polarized microtubule networks to direct the secretion of ECM components and construct the mammalian c...

Immune function and dysfunction are determined by lymphoid tissue efficacy

“…Maturing stromal cells generate chemoattractant gradients that support the separation of lymphocyte niches ( Bénézech et al, 2010 ). The fibroblastic stroma composes an interconnected cellular network, termed the FRC network, which confines a bundled extracellular matrix (ECM) through which lymph fluid from peripheral tissues is filtered ( Acton et al, 2021 ). The unique structure of lymph nodes therefore confers effective communication between peripheral tissues, leukocytes and the stromal cell architecture.…”

“…Lymph nodes constantly filter draining lymph via a conduit network of aligned ECM fibrils ensheathed by FRCs ( Kaldjian et al, 2001 ; Sixt et al, 2005 ). The containment of draining lymph by the FRC network allows for the controlled sensing of soluble mediators from peripheral tissues, but also provides a route to secrete antibodies and other lymphoid tissue-derived molecules out of the lymph node ( Acton et al, 2021 ; Thierry et al, 2018 ). The ECM can also retain chemokines such as CXCL13 to preserve B cells within the follicular region by creating a chemokine gradient ( Cosgrove et al, 2020 ).…”

Information flow in the spatiotemporal organization of immune responses*

“…Imaging studies by us and others have demonstrated that drainage of antigens and other soluble mediators from the inoculation site to LNs can happen within several minutes 13,14,99,196‐198 . Upon reaching the lymphatic sinuses, proteins and particles are physically separated based on molecular weight, with smaller antigens (<70 kDa) and fluids entering the LN conduit network distributed throughout the interfollicular regions and the T cell zone 197,199‐202 . These conduits are also directly connected to the nearby blood vessels, and within a few hours, fluid‐borne antigens, cytokines, and chemokines that entered the conduits are rapidly cleared out into the circulation.…”

“…13,14,99,[196][197][198] Upon reaching the lymphatic sinuses, proteins and particles are physically separated based on molecular weight, with smaller antigens (<70 kDa) and fluids entering the LN conduit network distributed throughout the interfollicular regions and the T cell zone. 197,[199][200][201][202] These conduits are also directly connected to the nearby blood vessels, and within a few hours, fluid-borne antigens, cytokines, and chemokines that entered the conduits are rapidly cleared out into the circulation. This can promote deposition of chemokines and inflammatory mediators on the lumen of high endothelial venules and lead to enhanced trafficking of immune cells into the reactive LNs.…”

Mathematical Modeling of Lymph Node Drainage Function by Neural Network

“…One of the first models of a paradigmatic LN was developed to study the 3D spatial cytokine (type I interferon) distribution with a stationary reaction-diffusion model [21]. The development of high-resolution imaging technologies enabled a detailed characterization of the topological and geometrical properties of LN structures, such as the fibroblastic reticular cell network [22], the conduit network [23,24] and the blood capillary network [25][26][27]. The generated quantitative data allowed to proceed with the development of a computational model of the LN geometry to incorporate the conduit and blood vascular networks [28].…”