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Dendritic cells (DCs) can be viewed as translators between innate and adaptive immunity. They integrate signals derived from tissue infection or damage and present processed antigen from these sites to naive T cells in secondary lymphoid organs while also providing multiple soluble and surface-bound signals that help to guide T cell differentiation. DC-mediated tailoring of the appropriate T cell programme ensures a proper cascade of immune responses that adequately targets the insult. Recent advances in our understanding of the different types of DC subsets along with the cellular organization and orchestration of DC and lymphocyte positioning in secondary lymphoid organs over time has led to a clearer understanding of how the nature of the T cell response is shaped. This Review discusses how geographical organization and ordered sequences of cellular interactions in lymph nodes and the spleen regulate immunity.

Lymph nodes (LNs) are strategically positioned at dedicated sites throughout the body to facilitate rapid and efficient immunity. Central to the structural integrity and framework of LNs, and the recruitment and positioning of leukocytes therein, are mesenchymal and endothelial lymph node stromal cells (LNSCs). Advances in the last decade have expanded our understanding and appreciation of LNSC heterogeneity, and the role they play in coordinating immunity has grown rapidly. In this review, we will highlight the functional contributions of distinct stromal cell populations during LN development in maintaining immune homeostasis and tolerance and in the activation and control of immune responses. Turley and Krishnamurty review new insights into lymph node stromal cells, a heterogeneous cell population that serves distinct functions during development, in maintaining lymphocyte homeostasis, and in coordinating immune responses.

Lymph nodes are secondary lymphoid organs in which immune responses of the adaptive immune system are initiated and regulated. Distributed throughout the body and embedded in the lymphatic system, local lymph nodes are continuously informed about the state of the organs owing to a constant drainage of lymph. The tissue-derived lymph carries products of cell metabolism, proteins, carbohydrates, lipids, pathogens and circulating immune cells. Notably, there is a growing body of evidence that individual lymph nodes differ from each other in their capacity to generate immune responses. Here, we review the structure and function of the lymphatic system and then focus on the factors that lead to functional heterogeneity among different lymph nodes. We will discuss how lymph node heterogeneity impacts on cellular and humoral immune responses and the implications for vaccination, tumour development and tumour control by immunotherapy.This Review from Wolfgang Kastenmüller and colleagues highlights the heterogeneity that exists among lymph nodes at different anatomical locations. The authors consider the factors that contribute to lymph node heterogeneity and explain the relevance of this for the immune response, particularly in the contexts of vaccination and cancer.

Lymph nodes (LNs) comprise two main structural elements: fibroblastic reticular cells that form dedicated niches for immune cell interaction and capsular fibroblasts that build a shell around the organ. Immunological challenge causes LNs to increase more than tenfold in size within a few days. Here, we characterized the biomechanics of LN swelling on the cellular and organ scale. We identified lymphocyte trapping by influx and proliferation as drivers of an outward pressure force, causing fibroblastic reticular cells of the T-zone (TRCs) and their associated conduits to stretch. After an initial phase of relaxation, TRCs sensed the resulting strain through cell matrix adhesions, which coordinated local growth and remodeling of the stromal network. While the expanded TRC network readopted its typical configuration, a massive fibrotic reaction of the organ capsule set in and countered further organ expansion. Thus, different fibroblast populations mechanically control LN swelling in a multitier fashion.Sixt and colleagues show that different fibroblast populations in the lymph node mechanically control its swelling in a multitier fashion.

Emergent physical properties of tissues are not readily understood by reductionist studies of their constituent cells. Here, we show molecular signals controlling cellular, physical, and structural properties and collectively determine tissue mechanics of lymph nodes, an immunologically relevant adult tissue. Lymph nodes paradoxically maintain robust tissue architecture in homeostasis yet are continually poised for extensive expansion upon immune challenge. We find that in murine models of immune challenge, cytoskeletal mechanics of a cellular meshwork of fibroblasts determine tissue tension independently of extracellular matrix scaffolds. We determine that C-type lectin-like receptor 2 (CLEC-2)–podoplanin signaling regulates the cell surface mechanics of fibroblasts, providing a mechanically sensitive pathway to regulate lymph node remodeling. Perturbation of fibroblast mechanics through genetic deletion of podoplanin attenuates T cell activation. We find that increased tissue tension through the fibroblastic stromal meshwork is required to trigger the initiation of fibroblast proliferation and restore homeostatic cellular ratios and tissue structure through lymph node expansion.Acton and colleagues examine the mechanics of lymph node swelling during the course of an immune response. They find tissue tension regulates fibroblastic reticular cell (FRC) proliferation during lymph node expansion and that podoplanin (PDPN)–CLEC-2 signaling in FRCs regulates this process, which in turn regulates T cell activation.

Intravital confocal microscopy and two-photon microscopy are powerful tools to explore the dynamic behavior of immune cells in mouse lymph nodes (LNs), with penetration depth of ~100 and ~300 μm, respectively. Here, we used intravital three-photon microscopy to visualize the popliteal LN through its entire depth (600–900 μm). We determined the laser average power and pulse energy that caused measurable perturbation in lymphocyte migration. Long-wavelength three-photon imaging within permissible parameters was able to image the entire LN vasculature in vivo and measure CD8+ T cells and CD4+ T cell motility in the T cell zone over the entire depth of the LN. We observed that the motility of naive CD4+ T cells in the T cell zone during lipopolysaccharide-induced inflammation was dependent on depth. As such, intravital three-photon microscopy had the potential to examine immune cell behavior in the deeper regions of the LN in vivo.Choe and colleagues show that intravital three-photon microscopy can be used to visualize the popliteal LN in mice and measure CD8+ T cells and CD4+ T cell motility through this paper shows T cell motility in the entire depthof T cell zone by ~635 um.

Older people are particularly susceptible to infectious and neoplastic diseases of the lung and it is unclear how lifelong exposure to environmental pollutants affects respiratory immune function. In an analysis of human lymph nodes (LNs) from 84 organ donors aged 11–93 years, we found a specific age-related decline in lung-associated, but not gut-associated, LN immune function linked to the accumulation of inhaled atmospheric particulate matter. Increasing densities of particulates were found in lung-associated LNs with age, but not in the corresponding gut-associated LNs. Particulates were specifically contained within CD68 + CD169 − macrophages, which exhibited decreased activation, phagocytic capacity, and altered cytokine production compared with non-particulate-containing macrophages. The structures of B cell follicles and lymphatic drainage were also disrupted in lung-associated LNs with particulates. Our results reveal that the cumulative effects of environmental exposure and age may compromise immune surveillance of the lung via direct effects on immune cell function and lymphoid architecture. Carbon-containing particulates accumulate with age in a subset of macrophages in human lung-associated lymph nodes, decrease macrophage phagocytic capacity and turnover and disrupt lymphoid tissue structure, potentially compromising adaptive immune responses.

Key Points T follicular helper (T FH ) cells are a phenotypically distinct subset of activated T cells that specializes in promoting germinal centre reactions that support B cell proliferation, somatic hypermutation and class-switch recombination. T FH cell development is regulated by a suite of transcriptional factors in conjunction with the master controller B cell lymphoma 6 (BCL-6). The classical cytokine-centric 'instructional' paradigm of T helper cell differentiation cannot fully explain how T FH cells develop and function. Key features of T FH cells are dictated by their dynamic interactions with cognate and bystander B cells and shaped by the tissue environment they traverse during distinct spatiotemporal stages of T cell-dependent B cell responses. Chance escape from an inhibitory tissue milieu and chance encounter with a conducive environment underlies the development of T FH cells. T FH cells contribute to the development of memory CD4 + T cell populations, and progression through an intermediate T FH cell stage may even be the predominant pathway for the formation of central memory T cell populations. A model of default T FH cell development with inherent spatiotemporal stochasticity is proposed. This Review discusses our current understanding of the development and functions of follicular helper T (T FH ) cells. The author explains how these cells do not fit with the classical instructional model of helper T cell differentiation and, instead, proposes a model of default T FH cell development with inherent spatiotemporal stochasticity. T follicular helper (T FH ) cells play a crucial part in the development of humoral immunity by controlling the formation of, and the cellular reactions that occur in, germinal centres. Within these organized lymphoid tissue microstructures, B cells proliferate and somatically mutate to produce long-lived, high-affinity plasma cells and memory B cells. T FH cells exhibit unique molecular, cellular and tissue-dynamic features that are integral to their development and function but that are not necessarily compatible with the classical paradigm of effector CD4 + T cell differentiation. Here, I discuss recent advances in T FH cell biology and their implications for our understanding of T cell differentiation and memory in humoral immunity from spatiotemporal and functional perspectives.

A significant fraction of the total immune cells in the body are located in several hundred lymph nodes, in which lymphocyte accumulation, activation and proliferation are organized. Therefore, targeting lymph nodes provides the possibility to directly deliver drugs to lymphocytes and lymph node-resident cells and thus to modify the adaptive immune response. However, owing to the structure and anatomy of lymph nodes, as well as the distinct localization and migration of the different cell types within the lymph node, it is difficult to access specific cell populations by delivering free drugs. Materials can be used as instructive delivery vehicles to achieve accumulation of drugs in the lymph nodes and to target specific lymph node-resident cell subtypes. In this Review, we describe the compartmental architecture of lymph nodes and the cell and fluid transport mechanisms to and from lymph nodes. We discuss the different entry routes into lymph nodes and how they can be explored for drug delivery, including the lymphatics, blood capillaries, high endothelial venules, cell-mediated pathways, homing of circulating lymphocytes and direct lymph node injection. We examine different nanoscale and microscale materials for the targeting of specific immune cells and highlight their potential for the treatment of immune dysfunction and for cancer immunotherapy. Finally, we give an outlook to the field, exploring how lymph node targeting can be improved by the use of materials. Nanoscale and microscale materials can be used as drug delivery vehicles to target specific lymph node-resident cell subtypes for immunotherapy. In this Review, the authors discuss the transport mechanisms to and from lymph nodes and how they can be explored for drug delivery.

Key Points Fibroblastic reticular cells (FRCs) are heterogeneous stromal cells. Subsets of FRCs include: T cell zone reticular cells that produce interleukin-7 (IL-7) to support naive T cells; resident and inducible B cell zone reticular cells that support naive B cells and follicle integrity; pericytic FRCs that support high endothelial venule (HEV) barrier function; follicular dendritic cells (FDCs) that support germinal centre function; and marginal reticular cells that can differentiate into FDCs. Crucial checkpoints in mesenchymal stromal cell development are retinoic acid signalling to mesenchymal progenitor cells, which creates the lymph node anlage, followed by the attraction of lymphotoxin ligand-bearing group 3 innate lymphoid cells (usually mediated by CXC-chemokine ligand 13 (CXCL13)). Lymphotoxin-β receptor (LTβR) signalling to mesenchymal precursor cells results in the development of CC-chemokine ligand 19 (CCL19) + CCL21 + CXCL13 + receptor activator of NF-κB ligand (RANKL) + LTβR + mucosal vascular addressin cell adhesion molecule 1 (MADCAM1) + lymphoid tissue organizer cells (LTo cells). Although it is still unclear precisely how LTo cells relate to mature FRCs, an immature FRC subset has been identified that requires LTβR signalling for the acquisition of an immunologically mature phenotype. FRCs give lymph nodes the flexibility to stretch and to contract to accommodate the trapping of naive lymphocytes during an active immune response. Podoplanin (PDPN) maintains tension in the FRC network during homeostatic conditions, and this function is inhibited during an immune response when an influx of dendritic cells expressing C-type lectin domain family 1 member B (commonly known as CLEC2) inhibits PDPN-mediated FRC contractility. During a chronic infection such as with HIV-1, regulatory T cells upregulate transforming growth factor-β1 (TGFβ1) production, which signals to FRCs to markedly increase their extracellular matrix production. Naive T cells can no longer physically contact FRCs and lose access to IL-7, which results in widespread T cell death and prolonged immunodeficiency. Therapeutic advances seeking to mimic or target FRC function include antifibrotic drugs to reverse lymph node fibrosis, the administration of recombinant IL-7 to support T cell recovery after immunodepletion, and the use of FRCs as a putative anti-inflammatory cell therapy. Fibroblastic reticular cells — which are immunologically specialized myofibroblasts of mesenchymal origin — create a network within lymph nodes that is essential for immunological health through interactions with B cells, T cells, dendritic cells and high endothelial venules. Over the past decade, a series of discoveries relating to fibroblastic reticular cells (FRCs) — immunologically specialized myofibroblasts found in lymphoid tissue — has promoted these cells from benign bystanders to major players in the immune response. In this Review, we focus on recent advances regarding the immunobiology of lymph node-derived FRCs, presenting an updated view of crucial checkpoints during their development and their dynamic control of lymph node expansion and contraction during infection. We highlight the robust effects of FRCs on systemic B cell and T cell responses, and we present an emerging view of FRCs as drivers of pathology following acute and chronic viral infections. Lastly, we review emerging therapeutic advances that harness the immunoregulatory properties of FRCs.