Talk:Lymph Node Development

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Cite this page: Hill, M.A. (2021, November 30) Embryology Lymph Node Development. Retrieved from


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Pubmed Central Images - Lymph Node Development | Pubmed Central Images - Lymph Node


Trends Immunol. 2019 Jan;40(1):35-48. doi: 10.1016/ Epub 2018 Nov 27.

Subcapsular Sinus Macrophages: The Seat of Innate and Adaptive Memory in Murine Lymph Nodes

Moran I, Grootveld AK, Nguyen A & Phan TG. (2019). Subcapsular Sinus Macrophages: The Seat of Innate and Adaptive Memory in Murine Lymph Nodes. Trends Immunol. , 40, 35-48. PMID: 30502023 DOI.

Moran I1, Grootveld AK2, Nguyen A3, Phan TG4. Author information Abstract Subcapsular sinus (SCS) macrophages are strategically positioned at the lymph-tissue interface in the lymph node to trap and present antigen to B cells. Recent murine data has shown that SCS macrophages also prevent the systemic spread of lymph-borne pathogens and are capable of activating a diverse range of innate effector and adaptive memory cells, including follicular memory T cells and memory B cells (Bmems), that are either pre-positioned or rapidly recruited to the subcapsular niche following infection and inflammation. Furthermore, Bmems are rapidly reactivated to differentiate into plasma cells in subcapsular proliferative foci (SPF). Thus, understanding how SCS macrophages coordinate both innate and adaptive memory responses in the subcapsular niche can provide new opportunities to bolster immunity against pathogens and cancer. Copyright © 2018 Elsevier Ltd. All rights reserved. PMID: 30502023 DOI: 10.1016/


A Fresh View on Lymph Node Organogenesis

Onder L & Ludewig B. (2018). A Fresh View on Lymph Node Organogenesis. Trends Immunol. , 39, 775-787. PMID: 30150089 DOI.

Lymph nodes (LNs) are strategically positioned outposts of the immune system that underpin regional immune surveillance. The current model describing LN formation in mice is based on a two cell-type interaction scheme with lymphoid tissue inducer cells regulating the activation of mesenchymal lymphoid tissue organizer cells. We highlight here the key role of lymphatic endothelial cells during the initiation of LN formation. The involvement of lymphatic endothelial cells as an additional organizer cell type in LN organogenesis unveils multiple control levels that govern the generation of lymphoid organs. Moreover, the linkage between lymphangiogenic and lymphvasculogenic processes and guidance of the accumulation and activation of lymphoid tissue inducer cells in the embryo suggests that LN formation may be driven on demand by developing organ systems. Copyright © 2018 Elsevier Ltd. All rights reserved. KEYWORDS: development; fibroblastic reticular cells; innate lymphoid cells; lymphatic endothelial cells; lymphoid tissue inducer cells; secondary lymphoid organs; stromal cells

Development of the LYVE-1 gene with an acidic-amino-acid-rich (AAAR) domain in evolution is associated with acquisition of lymph nodes and efficient adaptive immunity

J Cell Physiol. 2018 Apr;233(4):2681-2692. doi: 10.1002/jcp.26159. Epub 2017 Oct 4.

Huang SS1, Li YW2, Wu JL2, Johnson FE3, Huang JS4.

Abstract CRSBP-1 (mammalian LYVE-1) is a membrane glycoprotein highly expressed in lymphatic endothelial cells (LECs). It has multiple ligands, including hyaluronic acid (HA) and growth factors/cytokines (e.g., PDGF-BB and VEGF-A) containing CRS motifs (clusters of basic amino-acid residues). The ligand binding activities are mediated by Link module and acidic-amino-acid-rich (AAAR) domains, respectively. These CRSBP-1/LYVE-1 ligands have been shown to induce opening of lymphatic intercellular junctions in LEC monolayers and in lymphatic vessels in wild-type mice. We hypothesize that CRSBP-1/LYVE-1 ligands, particularly CRS-containing growth factors/cytokines, are secreted by immune and cancer cells for lymphatic entry during adaptive immune responses and lymphatic metastasis. We have looked into the origin of the Link module and AAAR domain of LYVE-1 in evolution and its association with the development of lymph nodes and efficient adaptive immunity. Lymph nodes represent the only major recent innovation of the adaptive immune systems in evolution particularly to mammals and bird. Here we demonstrate that the development of the LYVE-1 gene with the AAAR domain in evolution is associated with acquisition of lymph nodes and adaptive immunity. LYVE-1 from other species, which have no lymph nodes, lack the AAAR domain and efficient adaptive immunity. Synthetic CRSBP-1 ligands PDGF and VEGF peptides, which contain the CRS motifs of PDGF-BB and VEGF-A, respectively, specifically bind to CRSBP-1 but do not interact with either PDGFβR or VEGFR2. These peptides function as adjuvants by enhancing adaptive immunity of pseudorabies virus (PRV) vaccine in pigs. These results support the notion that LYVE-1 is involved in adaptive immunity in mammals.

KEYWORDS: LYVE-1 evolution; adaptive immunity; adjuvants; lymph nodes PMID: 28833090 PMCID: PMC6123220 DOI: 10.1002/jcp.26159

Expression of Pref-1 and Related Chemokines during the Development of Rat Mesenteric Lymph Nodes

Biomed Environ Sci. 2018 Jul;31(7):507-514. doi: 10.3967/bes2018.068.

Peng Y1, Jia LM1, Li BX2, Xie LP1, Xie ZJ1, Zheng JH1. Author information Abstract OBJECTIVE: The aim of this study was to investigate the ability of Pref-1+ adipocyte progenitor cells to mobilize into mesenteric lymph nodes (MLNs) and the dynamic expression of related chemokines during the development of rat MLNs.

METHODS: Immunohistochemical analyses were used to detect the expression of Pref-1 and related chemokines. Transmission electron microscopy (TEM) was used to observe the changes in ultrastructure of MLNs.

RESULTS: Cells containing lipid droplets were found in all rat MLNs at embryonic day (E) 18.5, 2 and 6 weeks (w) after birth, and they were similar to fibroblastic reticular cells (FRCs) or follicular dendritic cells (FDCs) under TEM. Pref-1+ adipocyte progenitor cells were found in all MLNs. The expression level of Pref-1 was significantly increased at 2 w after birth and decreased at 6 w after birth. The tendency of Cxcl12 expression was consistent with that of Pref-1 and was positively correlated with the expression of Pref-1 (P < 0.01; r = 0.897). At E18.5, Cxcl13, and Ccr7 were significantly expressed in the MLN anlage, but the expression level of Ccl21 was low. The expression level of Cxcl13, Ccr7, and Ccl21 in MLN were significantly increased at 2 w after birth (P < 0.05), while the expression of Ccr7 and Ccl21 were significantly decreased at 6 w after birth (P < 0.05).

CONCLUSION: Adipocyte progenitor cells are involved in the rat MLNs development through differentiation into FRC and FDC. The expression of the relevant chemokines during the development of MLNs is dynamic and may be related to the maintenance of lymph nodes self-balance state.

Copyright © 2018 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

KEYWORDS: Adipocyte progenitor cells; Chemokines; Development; Mesenteric lymph nodes; Rat; Ultrastructure PMID: 30145985 DOI: 10.3967/bes2018.068

Morphometric development of sheep (Ovis aries) lymph nodes in fetal period

Vet Res Forum. 2018 Spring;9(2):121-128. doi: 10.30466/VRF.2018.30833. Epub 2018 Jun 15.

Khaksary-Mahabady M1, Khazaeel K1, Pourmahdi Borujeni M2, Yazdanjoo B3.


Immune system plays crucial role in body and lymph nodes are essential parts of this system for combating pathogens. However, no study has ever been conducted on morphometric development of sheep lymph nodes in fetal period. Thus, this study attempted to examine the morphometric characteristics of a number of important lymph nodes of some lymphocenters of sheep during fetal period. To this end, 60 pieces of sheep fetuses collected from Ahvaz slaughterhouse were fixated in 10% formalin and then divided into four categories based on crown-rump length (CRL) following gender and weight determinations. Mandibular, caudal superficial cervical (prescapular), caudal mediastinum, jejunal mesenteric and popliteal lymph nodes were evaluated in five lymphocenters of head, neck, thoracic cavity, abdominal viscera and pelvic limbs, respectively. In each sample, nodes formation was visually checked and in cases of nodes formation, they were measured in terms of weight, length, width and thickness and collected data were statistically analyzed. The longest and shortest fetal CRLs were found to be 48.50 cm and 3.50 cm, respectively. Gender had no effect on study parameters in 32 male and 28 female fetuses. Study of sheep fetuses' lymph nodes revealed no macroscopic lymph node development by day 45, while all nodes were observable after the day 59. The shortest lymph node was mandibular node and the longest one was caudal mediastinum. Based on the results, it seemed that although the size of lymph nodes grows by age, this increase is not the same for all nodes and groups.

KEYWORDS: Fetus; Lymph nodes; Morphometric development; Sheep PMID: 30065800 PMCID: PMC6047582 DOI: 10.30466/VRF.2018.30833


Lymph Node Stroma Dynamics and Approaches for Their Visualization

Trends Immunol. 2017 Feb 14. pii: S1471-4906(17)30019-4. doi: 10.1016/ [Epub ahead of print]

Gentek R1, Bajénoff M2.


Lymphoid stromal cells are best known as the architectural cells of lymphoid organs. For decades, they have been considered as inert elements of the immune system but this view has changed dramatically in recent years, when it was discovered that they are endowed with critical immunoregulatory functions. It is now accepted that without them, the adaptive immune response would be compromised, if not abrogated entirely. Here, we review the function of the major lymphoid stromal cell types; the way they remodel upon inflammation; discuss the available tools to track their behavior; and introduce several methodological approaches that we believe will help improving our knowledge of these pivotal cell types.

Copyright © 2017 Elsevier Ltd. All rights reserved.

PMID 28214099 DOI: 10.1016/


Persistence and Adaptation in Immunity: T Cells Balance the Extent and Thoroughness of Search

PLoS Comput Biol. 2016 Mar 18;12(3):e1004818. doi: 10.1371/journal.pcbi.1004818. eCollection 2016.

Fricke GM1, Letendre KA2, Moses ME1,2,3, Cannon JL4,5.


Effective search strategies have evolved in many biological systems, including the immune system. T cells are key effectors of the immune response, required for clearance of pathogenic infection. T cell activation requires that T cells encounter antigen-bearing dendritic cells within lymph nodes, thus, T cell search patterns within lymph nodes may be a crucial determinant of how quickly a T cell immune response can be initiated. Previous work suggests that T cell motion in the lymph node is similar to a Brownian random walk, however, no detailed analysis has definitively shown whether T cell movement is consistent with Brownian motion. Here, we provide a precise description of T cell motility in lymph nodes and a computational model that demonstrates how motility impacts T cell search efficiency. We find that both Brownian and Lévy walks fail to capture the complexity of T cell motion. Instead, T cell movement is better described as a correlated random walk with a heavy-tailed distribution of step lengths. Using computer simulations, we identify three distinct factors that contribute to increasing T cell search efficiency: 1) a lognormal distribution of step lengths, 2) motion that is directionally persistent over short time scales, and 3) heterogeneity in movement patterns. Furthermore, we show that T cells move differently in specific frequently visited locations that we call "hotspots" within lymph nodes, suggesting that T cells change their movement in response to the lymph node environment. Our results show that like foraging animals, T cells adapt to environmental cues, suggesting that adaption is a fundamental feature of biological search.

PMID 26990103 PMCID: PMC4798282 DOI: 10.1371/journal.pcbi.1004818


Lymph node fibroblastic reticular cells in health and disease

Nat Rev Immunol. 2015 Jun;15(6):350-61.

Fletcher AL, Acton SE, Knoblich K. Abstract

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.

PMID 25998961 PMCID: PMC5152733 DOI: 10.1038/nri3846

Two-photon microscopy for imaging germinal centers and T follicular helper cells

Methods Mol Biol. 2015;1291:63-75. doi: 10.1007/978-1-4939-2498-1_6.

Clatworthy MR1.

Abstract One of the principle features of immune cells is their dynamic nature. Lymphocytes circulate in the blood between secondary lymphoid organs and tissues in an effort to maximize the likelihood of a rapid and appropriate immune response to invading pathogens and tissue damage. Conventional experimental techniques such as histology and flow cytometry have greatly increased our understanding of immune cells, but in the last decade, two-photon microscopy has revolutionized our ability to interrogate the dynamic behavior of immune cells, a facet so critical to their function. Two-photon microscopy relies on the excitation of fluorophores by simultaneous application of two photons of longer wavelength light. This allows a greater depth of imaging with minimal photodamage. Thus, living tissues can be imaged, including immune cells in lymph nodes. This technique has been used to interrogate the events occurring in a germinal center response and the interactions between cells in the germinal center, including T follicular helper cells (Tfh), germinal center B cells, and follicular dendritic cells (FDC). Herein, a method is described by which the interactions between Tfh and B cells within a germinal center in a popliteal lymph node can be imaged in a live mouse.

PMID 25836302 DOI: 10.1007/978-1-4939-2498-1_6


Development of secondary lymphoid organs in relation to lymphatic vasculature

Adv Anat Embryol Cell Biol. 2014;214:81-91. doi: 10.1007/978-3-7091-1646-3_7.

van de Pavert SA1, Mebius RE.


Although the initial event in lymphatic endothelial specification occurs slightly before the initiation of lymph node formation in mice, the development of lymphatic vessels and lymph nodes occurs within the same embryonic time frame. Specification of lymphatic endothelial cells starts around embryonic day 10 (E10), followed by endothelial cell budding and formation of the first lymphatic structures. Through lymphatic endothelial cell sprouting these lymph sacs give rise to the lymphatic vasculature which is complete by E15.5 in mice. It is within this time frame that lymph node formation is initiated and the first structure is secured in place. As lymphatic vessels are crucially involved in the functionality of the lymph nodes, the recent insight that both structures depend on common developmental signals for their initiation provides a molecular mechanism for their coordinated formation. Here, we will describe the common developmental signals needed to properly start the formation of lymphatic vessels and lymph nodes and their interdependence in adult life.

PMID 24276888



Lymphoid tissue inducer cells: innate cells critical for CD4+ T cell memory responses?

Ann N Y Acad Sci. 2012 Jan;1247:1-15. doi: 10.1111/j.1749-6632.2011.06284.x. Epub 2012 Jan 19.

Lane PJ1, Gaspal FM, McConnell FM, Kim MY, Anderson G, Withers DR. Author information

Abstract Lymphoid tissue inducer cells (LTi) are a relatively new arrival on the immunological cellular landscape, having first been characterized properly only 15 years ago. They are members of an emerging family of innate lymphoid cells (ILCs). Elucidation of their function reveals links not only with the ancient innate immune system, but also with adaptive immune responses, in particular the development of lymph nodes and CD4(+) T cell memory immune responses, which on one hand underpin the success of vaccination strategies, and on the other hand drive many human immunologically mediated diseases. This perspective article is not an exhaustive account of the role of LTi in the development of lymphoid tissues, as there have been many excellent reviews published already. Instead, we combine current knowledge of genetic phylogeny and comparative immunology, together with classical mouse genetics, to suggest how LTi might have evolved from a primitive lymphocytic innate cell in the ancestral 500-million-year-old vertebrate immune system into a cell critical for adaptive CD4(+) T cell immune responses in mammals. © 2012 New York Academy of Sciences.

PMID 22260374

The origins, function, and regulation of T follicular helper cells

J Exp Med. 2012 Jul 2;209(7):1241-53. doi: 10.1084/jem.20120994.

Ma CS, Deenick EK, Batten M, Tangye SG. Source Immunology Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.


The generation of high-affinity antibodies (Abs) plays a critical role in the neutralization and clearance of pathogens and subsequent host survival after natural infection with a variety of microorganisms. Most currently available vaccines rely on the induction of long-lived protective humoral immune responses by memory B cells and plasma cells, underscoring the importance of Abs in host protection. Ab responses against most antigens (Ags) require interactions between B cells and CD4(+) T helper cells, and it is now well recognized that T follicular helper cells (Tfh) specialize in providing cognate help to B cells and are fundamentally required for the generation of T cell-dependent B cell responses. Perturbations in the development and/or function of Tfh cells can manifest as immunopathologies, such as immunodeficiency, autoimmunity, and malignancy. Unraveling the cellular and molecular requirements underlying Tfh cell formation and maintenance will help to identify molecules that could be targeted for the treatment of immunological diseases that are characterized by insufficient or excessive Ab responses.

PMID 22753927

Lymph node macrophages

J Innate Immun. 2012;4(5-6):424-36. doi: 10.1159/000337007. Epub 2012 Apr 4.

Gray EE, Cyster JG. Source Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143-0414, USA.

Abstract Lymph node (LN) macrophages have long been known for their efficient uptake of lymph-borne antigens. A convergence of studies on innate and adaptive immune responses has led to exciting recent advances in understanding their more specialized properties: presenting antigens to B cells, dendritic cells and T cells, producing trophic factors and cytokines, and, remarkably, being permissive for viral infection, a property critical for mounting anti-viral responses. LN macrophages have been traditionally divided into subsets based on their subcapsular sinus and medullary locations. Here, we classify LN macrophages into three subsets: subcapsular sinus macrophages, medullary sinus macrophages and medullary cord macrophages. We review the literature regarding the roles of these cells in innate and adaptive immune responses and requirements for their development. We also discuss challenges associated with their purification as well as the existence of additional heterogeneity among LN macrophages. Copyright © 2012 S. Karger AG, Basel.

PMID 22488251


Human lymph node development: An inflammatory interaction

Immunol Lett. 2011 Jul;138(1):4-6. doi: 10.1016/j.imlet.2011.02.008. Epub 2011 Feb 17.

Cupedo T. Author information

Abstract In the developing human fetus, lymph nodes and Peyer's patches are formed during the first and second trimester of pregnancy. The cells responsible for this process, lymphoid tissue inducer (LTi) cells, share a number of characteristics with Natural Killer (NK) cells and produce cytokines related to inflammation. Here I will discuss recent advances in our understanding of human lymph node development, in particular the characterization of LTi cells and the relationship of these innate lymphocytes to conventional NK cells. Copyright © 2011 Elsevier B.V. All rights reserved. PMID 2133368

Molecular programming of B cell memory

Nat Rev Immunol. 2011 Dec 9;12(1):24-34. doi: 10.1038/nri3128.

McHeyzer-Williams M, Okitsu S, Wang N, McHeyzer-Williams L. Source Department of Immunology and Microbial Sciences, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.


The development of high-affinity B cell memory is regulated through three separable phases, each involving antigen recognition by specific B cells and cognate T helper cells. Initially, antigen-primed B cells require cognate T cell help to gain entry into the germinal centre pathway to memory. Once in the germinal centre, B cells with variant B cell receptors must access antigens and present them to germinal centre T helper cells to enter long-lived memory B cell compartments. Following antigen recall, memory B cells require T cell help to proliferate and differentiate into plasma cells. A recent surge of information - resulting from dynamic B cell imaging in vivo and the elucidation of T follicular helper cell programmes - has reshaped the conceptual landscape surrounding the generation of memory B cells. In this Review, we integrate this new information about each phase of antigen-specific B cell development to describe the newly unravelled molecular dynamics of memory B cell programming.

PMID 22158414


Ontogeny of stromal organizer cells during lymph node development

J Immunol. 2010 Apr 15;184(8):4521-30. Epub 2010 Mar 17.

Bénézech C, White A, Mader E, Serre K, Parnell S, Pfeffer K, Ware CF, Anderson G, Caamaño JH. Source School of Immunity and Infection, Institute for BioMedical Research-Medical Research Council Centre for Immune Regulation, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.


The development of secondary lymphoid organs, such as lymph nodes (LNs), in the embryo results from the reciprocal action between lymphoid tissue inducer (LTi) cells and stromal cells. However, the initial events inducing LN anlagen formation before the LTi stromal cells cross-talk interactions take place are not fully elucidated. In this study, we show that the inguinal LN anlagen in mouse embryos developed from mesenchymal cells surrounding the lymph sacs, spherical structures of endothelial cells that bud from veins. Using inguinal and mesenteric LNs (mLNs), we provide evidence supporting a two-step maturation model for stromal cells: first, ICAM-1(-)VCAM-1(-) mesenchymal precursor cells become ICAM-1(int)VCAM-1(int) cells, in a process independent of LTi cells and lymphotoxin beta receptor (LTbetaR) signaling. The second step involves the maturation of ICAM-1(int)VCAM-1(int) cells to ICAM-1(high)VCAM-1(high) mucosal addressin cell adhesion molecule-1(+) organizer cells and depends on both LTi cells and LTbetaR. Addition of alphaLTbetaR agonist to LN organ cultures was sufficient to induce ICAM-1(int)VCAM-1(int) cells to mature. In LtbetaR(-/-) embryos, both inguinal and mLN stromal cells showed a block at the ICAM-1(int)VCAM-1(int) stage, and, contrary to inguinal LNs, mLNs persist longer and contained LTi cells, which correlated with the sustained gene expression of Il-7, Cxcl13, and, to a lesser degree, Ccl21. Taken together, these results highlight the importance of the signals and cellular interactions that induce the maturation of stromal cells and ultimately lead to the formation of lymphoid tissues.

PMID 20237296


Development of secondary lymphoid organs

Annu Rev Immunol. 2008;26:627-50. doi: 10.1146/annurev.immunol.26.021607.090257.

Randall TD1, Carragher DM, Rangel-Moreno J. Author information


Secondary lymphoid organs develop during embryogenesis or in the first few weeks after birth according to a highly coordinated series of interactions between newly emerging hematopoietic cells and immature mesenchymal or stromal cells. These interactions are orchestrated by homeostatic chemokines, cytokines, and growth factors that attract hematopoietic cells to sites of future lymphoid organ development and promote their survival and differentiation. In turn, lymphotoxin-expressing hematopoietic cells trigger the differentiation of stromal and endothelial cells that make up the scaffolding of secondary lymphoid organs. Lymphotoxin signaling also maintains the expression of adhesion molecules and chemokines that govern the ultimate structure and function of secondary lymphoid organs. Here we describe the current paradigm of secondary lymphoid organ development and discuss the subtle differences in the timing, molecular interactions, and cell types involved in the development of each secondary lymphoid organ.

PMID 18370924

Lymph sacs are not required for the initiation of lymph node formation

Vondenhoff MF, van de Pavert SA, Dillard ME, Greuter M, Goverse G, Oliver G, Mebius RE.

Development. 2009 Jan;136(1):29-34.

The lymphatic vasculature drains lymph fluid from the tissue spaces of most organs and returns it to the blood vasculature for recirculation. Before reaching the circulatory system, antigens and pathogens transported by the lymph are trapped by the lymph nodes. As proposed by Florence Sabin more than a century ago and recently validated, the mammalian lymphatic vasculature has a venous origin and is derived from primitive lymph sacs scattered along the embryonic body axis. Also as proposed by Sabin, it has been generally accepted that lymph nodes originate from those embryonic primitive lymph sacs. However, we now demonstrate that the initiation of lymph node development does not require lymph sacs. We show that lymph node formation is initiated normally in E14.5 Prox1-null mouse embryos devoid of lymph sacs and lymphatic vasculature, and in E17.5 Prox1 conditional mutant embryos, which have defective lymph sacs. However, subsequent clustering of hematopoietic cells within these developing lymph nodes is less efficient.

PMID 19060331


Structure and function of rat lymph nodes

Arch Histol Cytol. 2008 Sep;71(2):69-76.

Ohtani O, Ohtani Y.

Department of Anatomy, Faculty of Medicine and Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.


The lymph node comprises a critical crossroad for encounters between antigen presenting cells, antigens from lymph, and lymphocytes recruited into lymph nodes from the blood. The node consists of spaces lined with lymphatic endothelial cells and parenchyma. The former spaces can be divided into the subcapsular sinuses, lymphatic labyrinths in the deep cortex, intermediate sinuses, and medullary sinuses. The sponge-like framework of the node parenchyma is composed of collagen fibers invested with reticular cells. The parenchyma can be divided into the cortex, deep cortex, and medullary cord. Lymphocytes migrate from the node parenchyma into the lymphatic labyrinths in the deep cortex. Close to the labyrinths are high endothelial venules (HEVs), through which circulating lymphocytes enter the node parenchyma. HEVs strongly express Aquaporin-1, suggesting that HEVs are involved in the net absorption of water, but not protein, from lymph coming through afferent lymphatics. Many LYVE-1 positive sinus reticular cells (i.e., lymphatic endothelial cells) with attached macrophages form a network within the lumen of the medullary sinuses. Fluids and migrating cells arriving at the node preferentially flow through the subcapsular sinuses, intermediate sinuses, and medullary sinuses in this order. Fluids and migrating cells may also enter the cortex through gaps in the floor of the subcapsular sinuses.

PMID 18974599

Organogenesis of lymphoid tissues

Nat Rev Immunol. 2003 Apr;3(4):292-303. Mebius RE. Source Department of Molecular Cell Biology, VU University Medical Center, v.d. Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands. Erratum in Nat Rev Immunol. 2003 Jun;3(6):509.


The development of lymphoid organs depends on the correct expression of several molecules within a defined timeframe during ontogeny. Although this is an extremely complex process, with each secondary lymphoid tissue requiring subtly different signals, a common framework for lymphoid development is beginning to emerge. Drawing on studies of lymph nodes, Peyer's patches and nasal-associated lymphoid tissue, an integrative model of lymphoid-tissue development, involving adhesion molecules, cytokines and chemokines, which emphasizes the role of interactions between CD3-CD4+CD45+ 'inducer' cells and VCAM1+ICAM1+ stromal 'organizer' cells is presented.

PMID 12669020


A developmental switch in lymphocyte homing receptor and endothelial vascular addressin expression regulates lymphocyte homing and permits CD4+ CD3- cells to colonize lymph nodes

Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11019-24.

Mebius RE, Streeter PR, Michie S, Butcher EC, Weissman IL. Department of Pathology, Stanford University School of Medicine, CA 94305, USA.


IN adult mice, the dominant adhesion molecules involved in homing to lymph nodes are L-selectin homing receptors on lymphocytes and the peripheral lymph node addressins on specialized high endothelial venules. Here we show that, from fetal life through the first 24 hr of life, the dominant adhesion molecules are the mucosal addressin MAdCAM-1 on lymph node high endothelial venules and its counterreceptor, the Peyer's patch homing receptor, integrin alpha 4 beta 7 on circulating cells. Before birth, 40-70% of peripheral blood leukocytes are L-selectin-positive, while only 1-2% expresses alpha 4 beta 7. However, the fetal lymph nodes preferentially attract alpha 4 beta 7-expressing cells, and this can be blocked by fetal administration of anti-MAdCAM-1 antibodies. During fetal and early neonatal life, when only MAdCAM-1 is expressed on high endothelial venules, an unusual subset of CD4 + CD3- cells, exclusively expressing alpha 4 beta 7 as homing receptors, enters the lymph nodes. Beginning 24 hr after birth a developmental switch occurs, and the peripheral node addressins are upregulated on high endothelial venules in peripheral and mesenteric lymph nodes. This switch in addressin expression facilitates tissue-selective lymphocyte migration and mediates a sequential entry of different cell populations into the lymph nodes. PMID: 8855301


Vascular architecture of thymus and lymph nodes, blood vessels, transmural passage of lymphocytes, and cell-interactions

Scan Electron Microsc. 1981;(Pt 3):89-98.

Irino S, Takasugi N, Murakami T.


Postcapillary or high-endothelial venules were preferentially distributed at the cortico-medullary junction of the thymus. In the lymph nodes these venules were located in he paracortical area between cortex and medulla. The venules in the thymus were surrounded by the so-called perivascular spaces, while those in the lymph nodes were not clearly surrounded by this space. The walls of the thymus venules were fenestrated. The reticular sheets surrounding the perivascular spaces were also fenestrated. These fenestrations facilitated the transmural passage of thymocytes through the vessels. In the lymph nodes where the venules had few fenestrations, lymphocytes in transmural passages were usually suspended between the high- endothelial cells. The macrophages were preferentially located in reticular meshes of the paracortical areas, and most of these cells were in contact with lymphocytes. This might indicate that the paracortical areas are the main interaction sites of lymph node lymphocytes and macrophages. Observations on the casted samples are also reported.

PMID: 7330596


Ontogeny of human fetal lymph nodes

Am J Anat. 1975 Jan;142(1):15-27.

Bailey RP, Weiss L.


Developing lymph nodes from 30 human embryos and fetuses with crown-rump lengths (CRL) of 18 mm (5.6 wk) to 245 mm (26 wk) were examined by light microscopy. The nodes were embedded in araldite, and the sections examined were approximately 1 mu in thickness. The development of nodes was divided into three stages: 1. the lymphatic plexus and connective tissue invagination (30 mm to 67 mm CRL); 2. the early fetal lymph node (43 mm to ,5 mm CRL); and 3. the late fetal lymph node (CRL greater than 75 mm). The lymphatic plexus was formed by connective tissue invaginations and bridges which divided a lymph sac into a meshwork of channels and spaces. Connective tissue invaginations were endothelially-lined and were surrounded by lymphatic space. Reticular cells, macrophages, and blood vessels were found in these invaginations. Early fetal lymph nodes were formed from invaginations when the cellular density and lymphocyte content increased. The lymphatic space surrounding the early node was the developing subcapsular sinus. With further development the early node became packed with lymphocytes, increasing the cellular density and size of the node. The connective tissue surrounding the subcapsular sinus condensed to form the capsule. Afferent lymphatic vessels pierced the capsule. Capillaries, veins, postcapillary venules, and occasional arteries were found in early and late nodes.

PMID: 1167215

Light and electron microscopic studies of postcapillary venules in developing human fetal lymph nodes

Am J Anat. 1975 May;143(1):43-58.

Bailey RP, Weiss L.


Developing lymph nodes from 30 human fetuses with crownrump lengths (CRL) of 38 mm (8.7 wk) to 245 mm (26 wk) were studied by light and electron microscopy. Blood vessels that appear to be postcapillary venules (PCV) are present in nodes of 47 mm CRL and older fetuses. These venules first appear in nodes whehn the nodal population of lymphocytes is sparse. In these early nodes PCV are distributed randomly and consist of a low endothelium, underlying basal lamina and incomplete pericyte sheath. Early nodal PCV are distinguised from other nodal blood vessels by the presence of lymphocyte diapedesis and several luminal lymphocytes. In the late stages of nodal development PCV are the more common non-capillary blood vessel and appear in the parenchyma near the periphery of the node. Late nodal PCV are generally characterized by a cuboidal endothelium that is rich in Golgi apparatus, lysosomes and Weibel-Palade bodies. The lumen and wall of late nodal PCV contain lymphocytes. The relationship between the development of the parenchyma of fetal nodes and the appearance and activity of PCV, the passage of lymphocytes through the PCV wall and the fine structure of developing PCV are described. It is suggested that the lymphocytes that first appear in developing nodes, and the majority of the lymphocytes found in late nodes, migrate to the node via the blood vascular system and enter the nodal parenchyma by passing across PCV endothelium.

PMID: 165702


Ultrastructure of the normal lymph node.

Am J Pathol. 1971 Oct;65(1):1-24.

Nopajaroonsri C, Luk SC, Simon GT.

Abstract The "normal" lymph node has been studied by electron microscopy. The lymphoid tissue can be divided into three distinct zones. Zone 1 consists of loosely arranged cells surrounding the lymphatic sinuses and blood vessels. This is the only zone in which plasma cells are present. Zone 2 is surrounded by zone 1 and consists of compactly arranged cells in which lymphocytes predominate. Zone 3 (germinal center) appears only after antigenic stimulation. It is characterized by large, ribosome-rich cells and macrophages containing phagocytosed lymphocytes. These zones are arranged with their longest diameters pointing towards the hilus. Zone 1 is the longest and extends across the cortex, paracortex and medulla. Zone 2 spans across cortex and paracortex. Zone 3 usually is confined to the cortex. Our preliminary studies indicate that zone 1 is mainly bursal dependent, zone 2 is mainly thymic dependent and zone 3 is bursal dependent.

PMID: 5096365

Immunobiology Textbook

Immunobiology 5th edition The Immune System in Health and Disease Charles A Janeway, Jr, Paul Travers, Mark Walport, and Mark J Shlomchik.

Part I. An Introduction to Immunobiology and Innate Immunity

Part III. The Development of Mature Lymphocyte Receptor Repertoires

Links: Blue Histology - Lymph Nodes