Lymphatic system: An active pathway for immune protection

doi:10.1016/j.semcdb.2014.11.012

Seminars in Cell & Developmental Biology

Volume 38, February 2015, Pages 83-89

https://doi.org/10.1016/j.semcdb.2014.11.012 Get rights and content

Abstract

Lymphatic vessels are well known to participate in the immune response by providing the structural and functional support for the delivery of antigens and antigen presenting cells to draining lymph nodes. Recent advances have improved our understanding of how the lymphatic system works and how it participates to the development of immune responses. New findings suggest that the lymphatic system may control the ultimate immune response through a number of ways which may include guiding antigen/dendritic cells (DC) entry into initial lymphatics at the periphery; promoting antigen/DC trafficking through afferent lymphatic vessels by actively facilitating lymph and cell movement; enabling antigen presentation in lymph nodes via a network of lymphatic endothelial cells and lymph node stroma cell and finally by direct lymphocytes exit from lymph nodes. The same mechanisms are likely also important to maintain peripheral tolerance. In this review we will discuss how the morphology and gene expression profile of the lymphatic endothelial cells in lymphatic vessels and lymph nodes provides a highly efficient pathway to initiate immune responses. The fundamental understanding of how lymphatic system participates in immune regulation will guide the research on lymphatic function in various diseases.

Section snippets

Overview

Lymphatic vessels have three primary roles in normal human biology. The first is to maintain fluid balance. Fluid that leaks from blood vessels in peripheral tissues is transported through lymphatic vessels and returned to the blood circulation. This is important for regulating the amount and the composition of fluids in circulation and within peripheral tissues. The second role is to absorb dietary fats in the intestine and transport them back into the blood stream. The third function is to

Antigens entry into initial lymphatic vessels

The initial lymphatic vessels are composed of single layer of overlapping, oak leaf-shaped lymphatic endothelial cells expressing the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), a typical initial lymphatic endothelial cell marker [7]. Intercellular junction molecules form “button” shaped junctions, with flaps constituting the primary lymphatic valve system (Fig. 1B) [8]. Opening of these valves creates a “hole” of approximately 2–3 μm in diameter, which allows fluid to flow

Migrating DCs

Once soluble molecules, particles and cells reach the lymph node subcapsular sinus from afferent collecting lymphatic vessels, a number of complex steps take place in order to efficiently present antigen and induce adaptive immune responses. First, when entering lymph node subcapsular sinus, the migrating DCs need to transmigrate across the lymphatic endothelial cell layer to reach the lymph node T cell zone. The lymph node lymphatic endothelial cells are known to express CCL1, which binds to

Lymphocyte egress from lymph nodes

After traveling through the lymph node, lymph enters efferent lymphatic vessels, flows through the downstream lymph node(s) and eventually returns to the blood circulation via the subclavian veins. Lymphocytes enter lymph node via high endothelial venule cells and move to T cell or B cell areas. After immune surveillance, the naïve T cells as well as the antigen-activated effector or memory cells also exit the lymph node via efferent lymphatics, returning to the blood circulation and eventually

Lymphatic endothelial cells and peripheral tolerance

In the past several years, accumulating evidences show that lymphatic endothelial cells express peripheral tissue antigens, suggesting that they directly participate in immune regulation [5], [42], [43]. Lymphatic endothelial cells line up the lymph node sinus and are exposed to the incoming lymph. Lymph contains peripheral self-antigens released from tissue homeostatic turn over and metabolism as well as foreign antigens. Lymphatic endothelial cells express MHC class I and II molecules [44],

Lymphangiogenesis and immune regulation

The growth of lymphatic vessels, termed as lymphangiogenesis, is frequently observed in inflammatory diseases and cancer progression. The expanding lymphatic network presumably provides larger surface area for fluid or cell entry to the lymphatic vessels. However, the role of lymphangiogenesis in regulating the transport of lymph or cells remains unclear.

Conclusion

Lymphatic vessels serve as the channels sending peripheral antigens and immune cells to the draining lymph nodes to initiate proper immunity. During steady state, lymph nodes maintain peripheral tolerance. Upon activation, lymph nodes quickly initiate protective adaptive immunity to produce antibody, cytotoxic immune cells and memory against the invading foreign antigens. In the past several years, with the improvement of our knowledge on the mechanisms whereby an immune response is initiated

Conflict of interest

The authors have no conflict of interest.

Acknowledgement

This work was supported by a University of Calgary start-up funding to SL, provided by the Dianne & Irving Kipnes Foundation and grants from the National Institutes of Health (NIH HL096552) and the Canadian Institutes of Health Research to PYvdW.

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ReviewLymphatic system: An active pathway for immune protection

Abstract

Section snippets

Overview

Antigens entry into initial lymphatic vessels

Migrating DCs

Lymphocyte egress from lymph nodes

Lymphatic endothelial cells and peripheral tolerance

Lymphangiogenesis and immune regulation

Conclusion

Conflict of interest

Acknowledgement

Synchrony of high endothelial venules and lymphatic vessels revealed by immunization

J Immunol

Lymph node macrophages

J Innate Immun

The role of lymph node sinus macrophages in host defense

Ann N Y Acad Sci

Dendritic-cell trafficking to lymph nodes through lymphatic vessels

Nat Rev Immunol

Peripheral tolerance induction by lymph node stroma

Adv Exp Med Biol

Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity

Nat Rev Cancer

Normal lymphatic development and function in mice deficient for the lymphatic hyaluronan receptor LYVE-1

Mol Cell Biol

Functionally specialized junctions between endothelial cells of lymphatic vessels

J Exp Med

The lymph as a pool of self-antigens

Trends Immunol

Dendritic cell function in vivo during the steady state: a role in peripheral tolerance

Ann N Y Acad Sci

Monitoring cellular movement in vivo with photoconvertible fluorescence protein Kaede transgenic mice

Proc Natl Acad Sci U S A

Rapid leukocyte migration by integrin-independent flowing and squeezing

Nature

DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling

J Exp Med

Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels

J Exp Med

Impaired humoral immunity and tolerance in K14-VEGFR-3-Ig mice that lack dermal lymphatic drainage

J Immunol

Normal dendritic cell mobilization to lymph nodes under conditions of severe lymphatic hypoplasia

J Immunol

Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues

Nat Immunol

Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics

Nat Immunol

CCR7 is involved in the migration of neutrophils to lymph nodes

Blood

Neutrophils exhibit differential requirements for homing molecules in their lymphatic and blood trafficking into draining lymph nodes

J Immunol

Neutrophils rapidly migrate via lymphatics after Mycobacterium bovis BCG intradermal vaccination and shuttle live bacilli to the draining lymph nodes

Blood

Lymphatic smooth muscle: the motor unit of lymph drainage

Int J Biochem Cell Biol

Differential requirement for ROCK in dendritic cell migration within lymphatic capillaries in steady-state and inflammation

Blood

Role of CCR8 and other chemokine pathways in the migration of monocyte-derived dendritic cells to lymph nodes

J Exp Med

Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses

J Exp Med

Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization

J Exp Med

Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs

Annu Rev Immunol

The atypical chemokine receptor CCRL1 shapes functional CCL21 gradients in lymph nodes

Nat Immunol

Afferent lymph-derived T cells and DCs use different chemokine receptor CCR7-dependent routes for entry into the lymph node and intranodal migration

Nat Immunol

The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node

Immunity

Conduit for privileged communications in the lymph node

Immunity

Distinct dendritic cell populations sequentially present antigen to CD4T cells and stimulate different aspects of cell-mediated immunity

Immunity

Conduits mediate transport of low-molecular-weight antigen to lymph node follicles

Immunity

Lymph-borne chemokines and other low molecular weight molecules reach high endothelial venules via specialized conduits while a functional barrier limits access to the lymphocyte microenvironments in lymph node cortex

J Exp Med

Review
Lymphatic system: An active pathway for immune protection