Talk:SH Lecture - Lymphatic Structure and Organs

From Embryology


eMed LAF


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

Cellular and Molecular Immunology

with STUDENT CONSULT Online Access Abbas, Abul K.; Lichtman, Andrew H. H.; Pillai, Shiv

APA Citation - Abbas, Abul K.; Lichtman, Andrew H. H.; Pillai, Shiv (2014). Cellular and Molecular Immunology : with STUDENT CONSULT Online Access. Retrieved from

Immunology : Introductory Textbook

Shetty, Nandini

APA Citation - Abbas, Abul K.; Lichtman, Andrew H. H.; Pillai, Shiv (2014). Basic Immunology : Functions and Disorders of the Immune System. Retrieved from

In this text, the author has tried to unfold before the student, the essence of immunology from its historic beginnings, to the understanding of basic concepts of host defence and onto the many clinical applications of this science. Immunology: Introductory Textbook, covers the topics of Immunobiology, Immunoglobulins, Immuno-response Mechanisms, Transplantation Immunology and Immunodeficiency Diseases, Immunopotentiation and Immuno-suppression, among others.


T cell and reticular network co-dependence in HIV infection

J Theor Biol. 2016 Feb 10. pii: S0022-5193(16)00081-3. doi: 10.1016/j.jtbi.2016.01.040.

Donovan GM1, Lythe G2.


Fibroblastic reticular cells (FRC) are arranged on a network in the T cell zone of lymph nodes, forming a scaffold for T cell migration, and providing survival factors, especially interleukin-7 (IL-7). Conversely, CD4+ T cells are the major producers of lymphotoxin-β (LT-β), necessary for the construction and maintenance of the FRC network. This interdependence creates the possibility of a vicious cycle, perpetuating loss of both FRC and T cells. Furthermore, evidence that HIV infection is responsible for collagenation of the network suggests that long term loss of network function might be responsible for the attenuated recovery in T cell count seen in HIV patients undergoing antiretroviral therapy (ART). We present computational and mathematical models of this interaction mechanism and subsequent naive CD4+ T-cell depletion in which (1) collagen deposition impedes access of naive T cells to IL-7 on the FRC and loss of IL-7 production by loss of FRC network itself, leading to the depletion of naive T cells through increased apoptosis; and (2) depletion of naive T cells as the source of LT-β on which the FRC depend for survival leads to loss of the network, thereby amplifying and perpetuating the cycle of depletion of both naive T cells and stromal cells. Our computational model explicitly includes an FRC network and its cytokine exchange with a heterogeneous T-cell population. We also derive lumped models, in terms of partial differential equations and reduced to ordinary differential equations, that provide additional insight into the mechanisms at work. The central conclusions are that (1) damage to the reticular network, caused by HIV infection is a plausible mechanism for attenuated recovery post-ART; (2) within this, the production of T cell survival factors by FRCs may be the key rate-limiting step; and (3) the methods of model reduction and analysis presented are useful for both immunological studies and other contexts in which agent-based models are severely limited by computational cost. Copyright © 2016 Elsevier Ltd. All rights reserved. KEYWORDS: FRC network; Fibroblastic reticular cells; Lymphocyte PMID 26874227

Enhancement of HIV-1 infection and intestinal CD4+ T cell depletion ex vivo by gut microbes altered during chronic HIV-1 infection

Retrovirology. 2016 Jan 14;13(1):5. doi: 10.1186/s12977-016-0237-1.

Dillon SM1, Lee EJ2, Donovan AM3, Guo K4, Harper MS5, Frank DN6,7, McCarter MD8, Santiago ML9, Wilson CC10.


BACKGROUND: Early HIV-1 infection is characterized by high levels of HIV-1 replication and substantial CD4 T cell depletion in the intestinal mucosa, intestinal epithelial barrier breakdown, and microbial translocation. HIV-1-induced disruption of intestinal homeostasis has also been associated with changes in the intestinal microbiome that are linked to mucosal and systemic immune activation. In this study, we investigated the impact of representative bacterial species that were altered in the colonic mucosa of viremic HIV-1 infected individuals (HIV-altered mucosal bacteria; HAMB) on intestinal CD4 T cell function, infection by HIV-1, and survival in vitro. Lamina propria (LP) mononuclear cells were infected with CCR5-tropic HIV-1BaL or mock infected, exposed to high (3 gram-negative) or low (2 gram-positive) abundance HAMB or control gram-negative Escherichia coli and levels of productive HIV-1 infection and CD4 T cell depletion assessed. HAMB-associated changes in LP CD4 T cell activation, proliferation and HIV-1 co-receptor expression were also evaluated. RESULTS: The majority of HAMB increased HIV-1 infection and depletion of LP CD4 T cells, but gram-negative HAMB enhanced CD4 T cell infection to a greater degree than gram-positive HAMB. Most gram-negative HAMB enhanced T cell infection to levels similar to that induced by gram-negative E. coli despite lower induction of T cell activation and proliferation by HAMB. Both gram-negative HAMB and E. coli significantly increased expression of HIV-1 co-receptor CCR5 on LP CD4 T cells. Lipopolysaccharide, a gram-negative bacteria cell wall component, up-regulated CCR5 expression on LP CD4 T cells whereas gram-positive cell wall lipoteichoic acid did not. Upregulation of CCR5 by gram-negative HAMB was largely abrogated in CD4 T cell-enriched cultures suggesting an indirect mode of stimulation. CONCLUSIONS: Gram-negative commensal bacteria that are altered in abundance in the colonic mucosa of HIV-1 infected individuals have the capacity to enhance CCR5-tropic HIV-1 productive infection and depletion of LP CD4 T cells in vitro. Enhanced infection appears to be primarily mediated indirectly through increased expression of CCR5 on LP CD4 T cells without concomitant large scale T cell activation. This represents a novel mechanism potentially linking intestinal dysbiosis to HIV-1 mucosal pathogenesis. PMID 26762145


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Previous Lectures: 2013 | 2012 | 2010 | 2008 (site deleted)

Gastrointestinal tract and the mucosal macrophage reservoir in HIV infection

Clin Vaccine Immunol. 2014 Nov;21(11):1469-73. doi: 10.1128/CVI.00518-14. Epub 2014 Sep 3.

Brown D1, Mattapallil JJ2.


The gastrointestinal tract (GIT) is a primary site for human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection, replication, and dissemination. After an initial explosive phase of infection, HIV establishes latency. In addition to CD4 T cells, macrophages are readily infected, which can persist for long periods of time. Though macrophages at various systemic sites are infected, those present in the GIT constitute a major cellular reservoir due to the abundance of these cells at mucosal sites. Here, we review some of the important findings regarding what is known about the macrophage reservoir in the gut and explore potential approaches being pursued in the field to reduce this reservoir. The development of strategies that can lead to a functional cure will need to incorporate approaches that can eradicate the macrophage reservoir in the GIT. Copyright © 2014, American Society for Microbiology. All Rights Reserved. PMID 25185575


Nature Immunology Animation Immunology in the Gut Mucosa

HIV-associated chronic immune activation

Immunol Rev. 2013 Jul;254(1):78-101. doi: 10.1111/imr.12079.

Paiardini M1, Müller-Trutwin M.


Systemic chronic immune activation is considered today as the driving force of CD4(+) T-cell depletion and acquired immunodeficiency syndrome (AIDS). A residual chronic immune activation persists even in HIV-infected patients in which viral replication is successfully inhibited by anti-retroviral therapy, with the extent of this residual immune activation being associated with CD4(+) T-cell loss. Unfortunately, the causal link between chronic immune activation and CD4(+) T-cell loss has not been formally established. This article provides first a brief historical overview on how the perception of the causative role of immune activation has changed over the years and lists the different kinds of immune activation characteristic of human immunodeficiency virus (HIV) infection. The mechanisms proposed to explain the chronic immune activation are multiple and are enumerated here, as well as the mechanisms proposed on how chronic immune activation could lead to AIDS. In addition, we summarize the lessons learned from natural hosts that know how to 'show AIDS the door', and discuss how these studies informed the design of novel immune modulatory interventions that are currently being tested. Finally, we review the current approaches aimed at targeting chronic immune activation and evoke future perspectives. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

PMID 23772616

Lymphatic vessels in health and disease

Wiley Interdiscip Rev Syst Biol Med. 2013 Jan-Feb;5(1):111-24. doi: 10.1002/wsbm.1201. Epub 2012 Dec 3.

Kesler CT1, Liao S, Munn LL, Padera TP. Author information


The lymphatic vasculature plays vital roles in tissue fluid balance, immune defense, metabolism, and cancer metastasis. In adults, lymphatic vessel formation and remodeling occur primarily during inflammation, development of the corpus luteum, wound healing, and tumor growth. Unlike the blood circulation, where unidirectional flow is sustained by the pumping actions of the heart, pumping actions intrinsic to the lymphatic vessels themselves are important drivers of lymphatic flow. This review summarizes critical components that control lymphatic physiology. Copyright © 2012 Wiley Periodicals, Inc.

PMID 23209022

Mouse Model of Lymph Node Metastasis via Afferent Lymphatic Vessels for Development of Imaging Modalities

PLoS One. 2013;8(2):e55797. doi: 10.1371/journal.pone.0055797. Epub 2013 Feb 6.

Li L, Mori S, Sakamoto M, Takahashi S, Kodama T. Source Department of Biomedical Engineering, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan ; Department of Diagnostic Radiology, Graduate School of Medicine, Tohoku University, Sendai, Japan. Abstract Animal studies of lymph node metastasis are constrained by limitations in the techniques available for noninvasive monitoring of the progression of lymph node metastasis, as well as difficulties in the establishment of appropriate animal models. To overcome these challenges, this study has developed a mouse model of inter-lymph-node metastasis via afferent lymphatic vessels for use in the development of imaging modalities. We used 14- to 18-week-old MRL/MpJ-/lpr/lpr (MRL/lpr) mice exhibiting remarkable systemic lymphadenopathy, with proper axillary lymph nodes (proper-ALNs) and subiliac lymph nodes (SiLNs) that are 6 to 12 mm in diameter (similar in size to human lymph nodes). When KM-Luc/GFP malignant fibrous histiocytoma-like cells stably expressing the firefly luciferase gene were injected into the SiLN, metastasis could be detected in the proper-ALN within 3 to 9 days, using in vivo bioluminescence imaging. The metastasis route was found to be via the efferent lymphatic vessels of the SiLN, and metastasis incidence depended on the number of cells injected, the injection duration and the SiLN volume. Three-dimensional contrast-enhanced high-frequency ultrasound imaging showed that the blood vessel volume and density in the metastasized proper-ALN significantly increased at 14 days after tumor cell inoculation into the SiLN. The present metastasis model, with lymph nodes similar in size to those of humans, has potential use in the development of ultrasound imaging with high-precision and high-sensitivity as well as other imaging modalities for the detection of blood vessels in lymph nodes during the progression of metastasis.

PMID 23405215


A decade of imaging cellular motility and interaction dynamics in the immune system

Science. 2012 Jun 29;336(6089):1676-81. doi: 10.1126/science.1221063.

Germain RN, Robey EA, Cahalan MD. Source Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.


To mount an immune response, lymphocytes must recirculate between the blood and lymph nodes, recognize antigens upon contact with specialized presenting cells, proliferate to expand a small number of clonally relevant lymphocytes, differentiate to antibody-producing plasma cells or effector T cells, exit from lymph nodes, migrate to tissues, and engage in host-protective activities. All of these processes involve motility and cellular interactions--events that were hidden from view until recently. Introduced to immunology by three papers in this journal in 2002, in vivo live-cell imaging studies are revealing the behavior of cells mediating adaptive and innate immunity in diverse tissue environments, providing quantitative measurement of cellular motility, interactions, and response dynamics. Here, we review themes emerging from such studies and speculate on the future of immunoimaging.

PMID 22745423

Developmental heterogeneity in DNA packaging patterns influences T-cell activation and transmigration

PLoS One. 2012;7(9):e43718. doi: 10.1371/journal.pone.0043718. Epub 2012 Sep 5.

Gupta S, Marcel N, Talwar S, Garg M, R I, Perumalsamy LR, Sarin A, Shivashankar GV. Source National Centre for Biological Sciences, Tata Institute for Fundamental Research, Bangalore, Karnataka, India.


Cellular differentiation programs are accompanied by large-scale changes in nuclear organization and gene expression. In this context, accompanying transitions in chromatin assembly that facilitates changes in gene expression and cell behavior in a developmental system are poorly understood. Here, we address this gap and map structural changes in chromatin organization during murine T-cell development, to describe an unusual heterogeneity in chromatin organization and associated functional correlates in T-cell lineage. Confocal imaging of DNA assembly in cells isolated from bone marrow, thymus and spleen reveal the emergence of heterogeneous patterns in DNA organization in mature T-cells following their exit from the thymus. The central DNA pattern dominated in immature precursor cells in the thymus whereas both central and peripheral DNA patterns were observed in naïve and memory cells in circulation. Naïve T-cells with central DNA patterns exhibited higher mechanical pliability in response to compressive loads in vitro and transmigration assays in vivo, and demonstrated accelerated expression of activation-induced marker CD69. T-cell activation was characterized by marked redistribution of DNA assembly to a central DNA pattern and increased nuclear size. Notably, heterogeneity in DNA patterns recovered in cells induced into quiescence in culture, suggesting an internal regulatory mechanism for chromatin reorganization. Taken together, our results uncover an important component of plasticity in nuclear organization, reflected in chromatin assembly, during T-cell development, differentiation and transmigration.

PMID 22957031

Figure 5. Schematic depicting the various stages in T-cell development and the observed differences in the nuclear organization.


Ex vivo imaging of T cells in murine lymph node slices with widefield and confocal microscopes

J Vis Exp. 2011 Jul 15;(53):e3054. doi: 10.3791/3054.

Salmon H, Rivas-Caicedo A, Asperti-Boursin F, Lebugle C, Bourdoncle P, Donnadieu E. Source Institut Cochin, Université Paris Descartes, CNRS (UMR 8104). Abstract

Naïve T cells continuously traffic to secondary lymphoid organs, including peripheral lymph nodes, to detect rare expressed antigens. The migration of T cells into lymph nodes is a complex process which involves both cellular and chemical factors including chemokines. Recently, the use of two-photon microscopy has permitted to track T cells in intact lymph nodes and to derive some quantitative information on their behavior and their interactions with other cells. While there are obvious advantages to an in vivo system, this approach requires a complex and expensive instrumentation and provides limited access to the tissue. To analyze the behavior of T cells within murine lymph nodes, we have developed a slice assay, originally set up by neurobiologists and transposed recently to murine thymus. In this technique, fluorescently labeled T cells are plated on top of an acutely prepared lymph node slice. In this video-article, the localization and migration of T cells into the tissue are analyzed in real-time with a widefield and a confocal microscope. The technique which complements in vivo two-photon microscopy offers an effective approach to image T cells in their natural environment and to elucidate mechanisms underlying T cell migration.

PMID 21775968

B cells within germinal centers migrate preferentially from dark to light zone

Proc Natl Acad Sci U S A. 2011 May 24;108(21):8755-60. doi: 10.1073/pnas.1101554108. Epub 2011 May 9.

Beltman JB, Allen CD, Cyster JG, de Boer RJ. Source Theoretical Biology, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.


One of the main questions in the field of imaging immune cell migration in living tissues is whether cells fulfill their functionality via random or nonrandom migration processes. For some applications, this issue has remained controversial even after publication of various imaging studies. A prime example is B-cell migration in germinal centers (GCs) where somatic hypermutation and clonal selection of B cells are thought to occur within morphologically distinct regions termed dark zone (DZ) and light zone (LZ). Here, we reanalyze a previously published dataset on GC B-cell migration, applying a sensitive analysis technique to detect directed migration and using a procedure to correct for a number of artifacts that frequently occur in time-lapse imaging experiments. Although B cells roughly perform a persistent random walk, we present evidence that they have a small preference (of on average about 0.2-0.3 μm min(-1)) to migrate from DZ to LZ, which is consistent with classical views of the GC reaction. This preference is most pronounced among a large subset of almost half of the B-cell population migrating along relatively straight tracks. Using a computational model to generate long-lasting B-cell tracks based on the experimental motility data (including the small directional preference), we predict a time course to travel from DZ to LZ of a few hours. This is consistent with experimental observations, and we show that at the observed cellular motility such a time course cannot be explained without the small preferential migration from DZ to LZ.

PMID 21555569

CD4+ T cell effects on CD8+ T cell location defined using bioluminescence

PLoS One. 2011 Jan 20;6(1):e16222. doi: 10.1371/journal.pone.0016222. Azadniv M, Bowers WJ, Topham DJ, Crispe IN. Source David H Smith Center for Microbiology and Immunology, Aab Institute for Biomedical Research, University of Rochester Medical Center, Rochester, New York, United States of America.


T lymphocytes of the CD8+ class are critical in delivering cytotoxic function and in controlling viral and intracellular infections. These cells are "helped" by T lymphocytes of the CD4+ class, which facilitate their activation, clonal expansion, full differentiation and the persistence of memory. In this study we investigated the impact of CD4+ T cells on the location of CD8+ T cells, using antibody-mediated CD4+ T cell depletion and imaging the antigen-driven redistribution of bioluminescent CD8+ T cells in living mice. We documented that CD4+ T cells influence the biodistribution of CD8+ T cells, favoring their localization to abdominal lymph nodes. Flow cytometric analysis revealed that this was associated with an increase in the expression of specific integrins. The presence of CD4+ T cells at the time of initial CD8+ T cell activation also influences their biodistribution in the memory phase. Based on these results, we propose the model that one of the functions of CD4+ T cell "help" is to program the homing potential of CD8+ T cells.

PMID 21283759


Peyer's Patches: The Immune Sensors of the Intestine

Int J Inflam. 2010 Sep 19;2010:823710. doi: 10.4061/2010/823710.

Jung C1, Hugot JP, Barreau F.


The gut-associated lymphoid tissue (GALT) consists of isolated or aggregated lymphoid follicles forming Peyer's patches (PPs). By their ability to transport luminal antigens and bacteria, PPs can be considered as the immune sensors of the intestine. PPs functions like induction of immune tolerance or defense against pathogens result from the complex interplay between immune cells located in the lymphoid follicles and the follicle-associated epithelium. This crosstalk seems to be regulated by pathogen recognition receptors, especially Nod2. Although TLR exerts a limited role in PP homeotasis, Nod2 regulates the number, size, and T-cell composition of PPs, in response to the gut flora. In turn, CD4(+) T-cells present in the PP are able to modulate the paracellular and transcellular permeabilities. Two human disorders, Crohn's disease and graft-versus-host disease are thought to be driven by an abnormal response toward the commensal flora. They have been associated with NOD2 mutations and PP dysfunction.

PMID 21188221

Two-photon microscopy analysis of leukocyte trafficking and motility

Semin Immunopathol. 2010 Sep;32(3):215-25. doi: 10.1007/s00281-010-0210-3. Epub 2010 Jul 6.

Okada T. Source Research Unit for Immunodynamics, RIKEN, Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.


During the last several years, live tissue imaging, in particular using two-photon laser microscopy, has advanced our understanding of leukocyte trafficking mechanisms. Studies using this technique are revealing distinct molecular requirements for leukocyte migration in different tissue environments. Also emerging from the studies are the ingenious infrastructures for leukocyte trafficking, which are produced by stromal cells. This review summarizes the recent imaging studies that provided novel mechanistic insights into in vivo leukocyte migration essential for immunosurveillance.

PMID 20603709

Below is the link to the electronic supplementary material.

Video 1(4.7M, mpg)

Migration of the B cell-T cell conjugate in the stromal cell network in the lymph node. The movie shows the 45-min time lapse images recorded every 30 s. Cognate antigen-specific B cells (green) and helper T cells (red) are stably conjugated. In cyan are primarily irradiation-resistant stromal cells. The mouse lymph node was imaged ex vivo by TPLM 36 h after immunization. Elapsed time is shown as hours/minutes/seconds. The image volume is 100 μm (x)×100 μm (y)×60 μm (z). The scale bar shows 30 μm on the nearest x-y plane from the viewpoint (MPG 4.71 MB)

Springer Open Choice are provided here courtesy of Springer


Regulation of immunological homeostasis in the respiratory tract

Nat Rev Immunol. 2008 Feb;8(2):142-52. doi: 10.1038/nri2236.

Holt PG, Strickland DH, Wikström ME, Jahnsen FL. Author information


The respiratory tract has an approximate surface area of 70 m2 in adult humans, which is in virtually direct contact with the outside environment. It contains a uniquely rich vascular bed containing a large pool of marginated T cells, and harbours a layer of single-cell-thick epithelial tissue through which re-oxygenation of blood must occur uninterrupted for survival. It is therefore not surprising that the respiratory tract is never more than a short step away from disaster. We have only a partial understanding of how immunological homeostasis is maintained in these tissues, but it is becoming clear that the immune system has evolved a range of specific mechanisms to deal with the unique problems encountered in this specialized microenvironment.

  • Under steady-state conditions, the leukocyte population in the alveolar space is dominated by alveolar macrophages (more than 90% of the total cell population), the remainder being mainly DCs and T cells.
  • The lung parenchyma also contains scattered macrophages, DCs and T cells, as well as B cells and mast cells, but no plasma cells.

PMID 18204469


Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells

Nature. 2007 Nov 1;450(7166):110-4. Epub 2007 Oct 14.

Junt T1, Moseman EA, Iannacone M, Massberg S, Lang PA, Boes M, Fink K, Henrickson SE, Shayakhmetov DM, Di Paolo NC, van Rooijen N, Mempel TR, Whelan SP, von Andrian UH.

Abstract Lymph nodes prevent the systemic dissemination of pathogens such as viruses that infect peripheral tissues after penetrating the body's surface barriers. They are also the staging ground of adaptive immune responses to pathogen-derived antigens. It is unclear how virus particles are cleared from afferent lymph and presented to cognate B cells to induce antibody responses. Here we identify a population of CD11b+CD169+MHCII+ macrophages on the floor of the subcapsular sinus (SCS) and in the medulla of lymph nodes that capture viral particles within minutes after subcutaneous injection. Macrophages in the SCS translocated surface-bound viral particles across the SCS floor and presented them to migrating B cells in the underlying follicles. Selective depletion of these macrophages compromised local viral retention, exacerbated viraemia of the host, and impaired local B-cell activation. These findings indicate that CD169+ macrophages have a dual physiological function. They act as innate 'flypaper' by preventing the systemic spread of lymph-borne pathogens and as critical gatekeepers at the lymph-tissue interface that facilitate the recognition of particulate antigens by B cells and initiate humoral immune responses. PMID: 17934446 DOI: 10.1038/nature06287


The mucosal immune system and HIV-1 infection

AIDS Rev. 2003 Oct-Dec;5(4):245-52.

Veazey R1, Lackner A.


Recent progress in HIV-1 and SIV pathogenesis has revealed that mucosal tissues, primarily the gastrointestinal tract, are major sites for early viral replication and CD4+ T-cell destruction, and may be the major viral reservoir, even in patients receiving HAART. This is likely attributable to the fact that the majority of mucosal CD4+ T-cells co-expressing chemokine receptors requited for HIV-1 entry, reside in mucosal tissues. Furthermore, the intestinal mucosal immune system is continuously bombarded by dietary antigens, resulting in continual lymphocyte activation, dissemination, and homing of these activated lymphocytes (including CCR5+CD4+ T-cells) throughout mucosal tissues. Thus, the intestinal immune system represents a very large target for HIV-infection, which is continually generating newly activated CD4+ T-cells that are the preferred target of infection. Thus, HIV-1 appears uniquely adapted to persist and thrive in the mucosal-tissue environment. The selective loss of intestinal CD4+ T-cells from immune-effector sites is also likely to explain, at least in part, the preponderance of opportunistic infections at mucosal sites. It is increasingly evident that effective therapies and vaccines must be directed towards eliminating HIV-1 in mucosal tissue reservoirs, protecting mucosal CD4+ T-cells and stimulating effective mucosal immune responses.

PMID 15012003


C-type lectins and sialyl Lewis X oligosaccharides. Versatile roles in cell-cell interaction

J Cell Biol. 1999 Nov 1;147(3):467-70.

Fukuda M, Hiraoka N, Yeh JC. Source Glycobiology Program, Cancer Research Center, The Burnham Institute, La Jolla, California 92037, USA.

Carbohydrates are major components of the outer surface of mammalian cells and these carbohydrates are very often characteristic of cell-types and developmental stages

Article includes HEV information.

PMID 10545492 [PubMed - indexed for MEDLINE] PMCID: PMC2151194

HEV Reviews




2012 Lecture Introduction

While the structure of the lymphatic system (lympha = clear water) is well described, there is much to still learn about the complex development and function of this "system".

  1. Immune - “monitor” of body surfaces, internal fluids
  2. Extracellular fluid - returns interstitial fluid to circulation
  3. Gastrointestinal tract - carries fat and fat-soluble vitamins

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

Blood Cell Numbers

The adult ranges of cells / 1 litre (l), total blood volume is about 4.7 to 5 litres. Blood Development | Blood Histology

Red Blood Cells

  • Male: 4.32 - 5.66 x 1012/l
  • Female: 3.88 - 4.99 x 1012/l

Leukocytes (white blood cells)

  • Male: 3.7 - 9.5 x 109/l
  • Female: 3.9 - 11.1 x 109/l


  • 1.8 - 8.9 x 109/l
    • Neutrophils: 1.5 - 7.4 x 109/l
    • Eosinophils: 0.02 - 0.67 x 109/l
    • Basophils: 0 - 0.13 x 109/l


  • Monocytes 0.21 - 0.92 x 109/l


  • 1.1 - 3.5 x 109/l
    • B-cells: 0.06 - 0.66 x 109/l
    • T-cells: 0.77 - 2.68 x 109/l
      • CD4+: 0.53 - 1.76 x 109/l
      • CD8+: 0.30 - 1.03 x 109/l
    • NK cells: 0.20 - 0.40 x 109/l


  • 140 - 440 x 109/l
    • not a cell, a cell fragment.

Anatomy of the Human Body Gray (1918 Historic anatomy is good, there are there are some functional inaccuracies).

Additional Images

Reciprocal interactions of the intestinal microbiota and immune system

Todays Lecture in the Online Textbooks

--Mark Hill 10:32, 24 February 2012 (EST) The following link to text and figures that relate to lymphatic structure and organs. Remember the Lecture is about structure/function and not a description of immunity (that will be covered elsewhere in the course).


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

Molecular Biology of the Cell

Medical Microbiology

Pubmed Bookshelf


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


  • Preface to the Fifth Edition
  • Acknowledgments
  • Icons Used Throughout the Book

Part I. An Introduction to Immunobiology and Innate Immunity

Part II. The Recognition of Antigen

  • Chapter 3. Antigen Recognition by B-cell and T-cell Receptors
    • The structure of a typical antibody molecule
    • The interaction of the antibody molecule with specific antigen
    • Antigen recognition by T cells
    • Summary to Chapter 3
    • General references
    • Section references
  • Chapter 4. The Generation of Lymphocyte Antigen Receptors
    • The generation of diversity in immunoglobulins
    • T-cell receptor gene rearrangement
    • Structural variation in immunoglobulin constant regions
    • Summary to Chapter 4
    • General references
    • Section references
  • Chapter 5. Antigen Presentation to T Lymphocytes
    • The generation of T-cell receptor ligands
    • The major histocompatibility complex and its functions
    • Summary to Chapter 5
    • General references
    • Section references

Part III. The Development of Mature Lymphocyte Receptor Repertoires

Part IV. The Adaptive Immune Response

  • Chapter 8. T Cell-Mediated Immunity
    • The production of armed effector T cells
    • General properties of armed effector T cells
    • T cell-mediated cytotoxicity
    • Macrophage activation by armed CD4 TH1 cells
    • Summary to Chapter 8
    • General references
    • Section references
  • Chapter 9. The Humoral Immune Response
    • B-cell activation by armed helper T cells
    • The distribution and functions of immunoglobulin isotypes
    • The destruction of antibody-coated pathogens via Fc receptors
    • Summary to Chapter 9
    • General references
    • Section references
  • Chapter 10. Adaptive Immunity to Infection
    • Infectious agents and how they cause disease
    • The course of the adaptive response to infection
    • The mucosal immune system
    • Immunological memory
    • Summary to Chapter 10
    • General references
    • Section references

Part V. The Immune System in Health and Disease

  • Chapter 11. Failures of Host Defense Mechanisms
    • Pathogens have evolved various means of evading or subverting normal host defenses
    • Inherited immunodeficiency diseases
    • Acquired immune deficiency syndrome
    • Summary to Chapter 11
    • General references
    • Section references
  • Chapter 12. Allergy and Hypersensitivity
    • The production of IgE
    • Effector mechanisms in allergic reactions
    • Hypersensitivity diseases
    • Summary to Chapter 12
    • General references
    • Section references
  • Chapter 13. Autoimmunity and Transplantation
    • Autoimmune responses are directed against self antigens
    • Responses to alloantigens and transplant rejection
    • Self-tolerance and its loss
    • Summary to Chapter 13
    • General references
    • Section references
  • Chapter 14. Manipulation of the Immune Response
    • Extrinsic regulation of unwanted immune responses
    • Using the immune response to attack tumors
    • Manipulating the immune response to fight infection
    • Summary to Chapter 14
    • General references
    • Section references
  • Chapter 15. Afterword
    • Evolution of the innate immune system
    • Evolution of the adaptive immune response
    • The importance of immunological memory in fixing adaptive immunity in the genome
    • Future directions of research in immunobiology
    • Summary of the Afterword


Molecular Biology of the Cell

Medical Microbiology

Search PubMed Databases immune system


Start Time/End Time: 10am to 11am Monday 28 February 2011 Clancy Auditorium eMed Link to Learning Activity - Lymphatic organs histology

Bookshelf links

old - MBoC Figure 24-3 Human lymphoid organs

new - MBoC Figure 24-3 Human lymphoid organs

Recent Research

Defining the quantitative limits of intravital two-photon lymphocyte tracking

Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12401-6. Epub 2011 Jul 6.

Textor J, Peixoto A, Henrickson SE, Sinn M, von Andrian UH, Westermann J. Source Institute for Theoretical Computer Science, University of Lübeck, 23562 Lübeck, Germany.


Two-photon microscopy has substantially advanced our understanding of cellular dynamics in the immune system. Cell migration can now be imaged in real time in the living animal. Strikingly, the migration of naive lymphocytes in secondary lymphoid tissue appears predominantly random. It is unclear, however, whether directed migration may escape detection in this random background. Using a combination of mathematical modeling and experimental data, we investigate the extent to which modern two-photon imaging can rule out biologically relevant directed migration. For naive T cells migrating in uninfected lymph nodes (LNs) at average 3D speeds of around 18 μm/min, we rule out uniform directed migration of more than 1.7 μm/min at the 95% confidence level, confirming that T cell migration is indeed mostly random on a timescale of minutes. To investigate whether this finding still holds for longer timescales, we use a 3D simulation of the naive T cell LN transit. A pure random walk predicts a transit time of around 16 h, which is in good agreement with experimental results. A directional bias of only 0.5 μm/min-less than 3% of the cell speed-would already accelerate the transit twofold. These results jointly strengthen the random walk analogy for naive T cell migration in LNs, but they also emphasize that very small deviations from random migration can still be important. Our methods are applicable to cells of any type and can be used to reanalyze existing datasets.

PMID 21734152

Stromal cell contributions to the homeostasis and functionality of the immune system

Nat Rev Immunol. 2009 Sep;9(9):618-29. Epub 2009 Jul 31.

Mueller SN, Germain RN. Source Department of Microbiology and Immunology, The University of Melbourne, Parkville, 3010 Victoria, Australia. Abstract A defining characteristic of the immune system is the constant movement of many of its constituent cells through the secondary lymphoid tissues, mainly the spleen and lymph nodes, where crucial interactions that underlie homeostatic regulation, peripheral tolerance and the effective development of adaptive immune responses take place. What has only recently been recognized is the role that non-haematopoietic stromal elements have in many aspects of immune cell migration, activation and survival. In this Review, we summarize our current understanding of lymphoid compartment stromal cells, examine their possible heterogeneity, discuss how these cells contribute to immune homeostasis and the efficient initiation of adaptive immune responses, and highlight how targeting of these elements by some pathogens can influence the host immune response.

PMID 19644499

Lymphatic vessels: structure and function

Isr Med Assoc J. 2011 Dec;13(12):762-8.

Rovenská E, Rovenský J. Source National institute of Rheumatic Diseases, Piestany, Slovak Republik. l ymphatic vessels are part of the lymphatic system. The ves- sels evolved phylogenetically only after it became necessary for multicellular organisms to remove fluids and proteins from tissue and return them to the bloodstream. In humans, the lymphatic system begins to develop between the sixth and seventh week of embryonic development, at a time when the cardiovascular system is already functioning.

PMID 22332449