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Lymphocyte Trafficking

Avi N Kogan, Ulrich H von Andrian

10.1002/cphy.cp020410

Source: Supplement 9: Handbook of Physiology, The Cardiovascular System, Microcirculation

Originally published: 2008

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Principles of Lymphocyte Recirculation
1.1 The Circulatory and Lymphatic Systems
1.2 Lymphocyte and dendritic cell subsets
2 Primary Lymphoid Organs
2.1 Thymus
2.2 Bone marrow
3 Secondary Lymphoid Organs
3.1 Peripheral lymph nodes
3.2 Peyer's patches
3.3 Mesenteric Lymph Nodes
3.4 Spleen
3.5 Other secondary lymphoid tissues
3.6 Imprinting of Tissue‐Specific Effector Lymphocytes
4 Lymphocyte Traffic to Non‐Lymphoid Tissues
4.1 Constitutive migration: immune surveillance
4.2 Inflammation
4.3 “Tertiary” lymphoid organs
Figure 1. Figure 1.

Major routes of lymphocyte trafficking. Lymphocytes arise from bone marrow‐derived hematopoietic progenitor cells (HPCs). A subset of HPCs. lymphoid progenitor cells, leave the BM and travel to the thymus, where they give primarily rise to naïve T cells (but also NK cells and dendritic cell subsets) that enter the blood. HPCs in the BM also give rise to B‐cell progenitors that differentiate into immature B cells, which travel to the spleen for final maturation. Naïve T cells and mature B cells recirculate through the body, reaching secondary lymphoid organs (SLO) via the blood and returning to the bloodstream directly (in spleen) or via lymph (elsewhere). Upon antigen encounter, lymphocytes are activated (primarily by antigen‐presenting dendritic cells) and proliferate within SLO. Effector T cells arising in SLO migrate to peripheral sites of inflammation: activated B cells differentiate into either memory B cells, which are thought to recirculate through SLO, or antibody‐secreting plasma cells, some of which lodge within the BM (long‐lived IgG‐producing cells), the spleen and medulla of lymph nodes (short‐lived IgG‐producing cells) and mucosal tissues (IgA‐producing cells). Long‐term protection (immunological memory) is provided by effector memory T cells, which patrol peripheral tissues; central memory T cells, which recirculate through SLO; and antibody‐secreting plasma cells. Here, primary lymphoid organs and SLO are italicized, while peripheral tissues appear in normal typeface. Trafficking routes of T cells, their progenitors and progeny are shown with black arrows: those of B cells, their progenitors and progeny are shown with gray arrows. (See page 8 in colour section at the back of the book)
Figure 2. Figure 2.

The multi‐step adhesion cascade and its essential molecular players. The top of this schematic diagram depicts the four distinct adhesion steps that leukocytes must undergo to accumulate in a blood vessel. Also shown are the predominant molecular determinants of each step on leukocytes (middle) and endothelial cells (bottom). A number of molecules can interact with more than one partner (symbolized by arrows). Leukocytes in the blood stream (arrows at left symbolize the laminar flow profile in microvessels) tether to endothelial cells and roll slowly downstream. Tethering is facilitated by leukocyte receptors that occur at high density on the tips of microvillous surface protrusions (L‐selectin, PSGL‐1, and α4 integrins), whereas subsequent rolling is not influenced by the topography of adhesion receptors. The most efficient tethering molecules are L‐ and P‐selectin. L‐selectin recognizes sulfated sialyl‐Lewisx‐like sugars (PNAd) in HEV and it also interact with other ligands on inflamed endothelial cells (not shown) and with PSGL‐1 on adherent leukocytes (broken arrow). PSGL‐1 binding to L‐ and P‐selectin requires decoration with sLex‐like sugar moieties in vicinity to an N‐terminal motif containing three tyrosines (Y) that must be sulfated. E‐selectin can also interact with PSGL‐1, but does not require sulfation and also recognizes other sLex‐bearing glycoconjugates. E‐selectin and the α4 integrins can tether some leukocytes, but their predominant function is to reduce rolling velocities. G‐protein‐coupled receptors, which uniformly feature seven transmembrane domains (7TMRs) on rolling cells can bind specific chemoattractants, such as a chemokine. This interaction provides an activating trasnmembrane signal that induces rapid activation of β2 and/or α4 integrins. The activated integrins then bind their ligands, members of the endothelial Ig superfamily. Note that α4 integrins can mediate activation‐independent rolling interactions as well as firm arrest. However, the latter function requires integrin activation (symbolized by the open conformation of the heterodimer).

Reprinted from Ref. 51. (See page 9 in colour section at the back of the book)
Figure 3. Figure 3.

Routes of lymphocyte trafficking through secondary lymphoid organs and other tissues. Antigen can first appear in the skin, mucosa, gut (alimentary tract), and blood. Lymphocyte recirculation through various secondary lymphoid organs gives them rapid access to antigen appearing by any of these means. The major routes of naïve and memory lymphocyte trafficking are shown. Here, secondary lymphoid organs are italicized, and other organs/tissues appear in regular typeface. Dark gray arrows represent travel through the circulation, while light gray arrows represent travel through lymphatics.

Reprinted from Scimone ML and von Andrian UH. Immunological homing and adhesion molecules. In Encyclopedia of Life Sciences. Chichester, UK: John Wiley and Sons Ltd., 2004. DOI: 10.1038/npg.els.0003990 (See page 9 in colour section at the back of the book)
Figure 4. Figure 4.

Lymph node anatomy, compartmentalization. and microcirculation. (A) as pointed out before, panel (A) appears to be corrupted. Background patterns are markedly distorted and different from the original Schematic drawing of a confocal micrograph of a murine inguinal LN. Major blood vessels, medulla, and cortex consisting of superficial B follicles (B) and the T‐cell area (T) containing high endothelial venules (HEV) are shown. (B) Confocal micrograph corresponding to the drawing in panel A. The microcirculation was visualized after i.v. injection of a mixture of green and red fluorescent dextrans. These plasma markers fill all microvessels. which appear yellow. The preparation is partly covered by fatty tissue, which diffracts fluorescent light emitted from the superficial epigastric vein resulting in a “bubbly” appearance. To identify the different lymphoid compartments, purified fluorescent B cells (gray) and T cells (dark gray) were injected i.v. 20h prior to this recording. After their entry into the LN via HEV, the homed cells segregate. B cells populate the more distal B follicles, whereas T cells remain in the paracortex. (C) A higher magnification of the boxed region in panel B illustrates the relationship of B and T cells and the microcirculation. (See page 10 in colour section at the back of the book)
Figure 5. Figure 5.

Schematic diagram of imprinting signals that direct primed T cells to the gut or skin. When naïve T cells are activated under the influence of retinoic acid (RA) they acquire a gut‐homing phenotype with high expression levels of the integrin α4β7 and the chemokine receptor CCR9. RA is produced by dendritic cells (DCs) in gut‐associated lymphoid tissues and also by intestinal epithelium and possibly by other sources. Simultaneously, RA suppresses T cell acquisition of skin‐homing molecules (E‐/P‐selectin ligands and CCR4). T‐cell activation in the absence of RA induces a preferential skin‐homing phenotype with high expression of E‐/P‐selectin ligands and CCR4. DC in skin‐draining peripheral lymph nodes (PLN DC) can generate additional specific imprinting signals, such as 1,25(OH)‐vitamin D3 and interleukin‐12, which together induce some T cells to express CCR10, a chemokine receptor that promotes T‐cell epidermotropism. Figure modified from Mora JR and von Andrian UH Retinoic acid: an educational “vitamin elixir” for gut‐seeking T cells. Immunity 21 (4): 458–460, 2004. (See page 10 in colour section at the back of the book)


Figure 1.

Major routes of lymphocyte trafficking. Lymphocytes arise from bone marrow‐derived hematopoietic progenitor cells (HPCs). A subset of HPCs. lymphoid progenitor cells, leave the BM and travel to the thymus, where they give primarily rise to naïve T cells (but also NK cells and dendritic cell subsets) that enter the blood. HPCs in the BM also give rise to B‐cell progenitors that differentiate into immature B cells, which travel to the spleen for final maturation. Naïve T cells and mature B cells recirculate through the body, reaching secondary lymphoid organs (SLO) via the blood and returning to the bloodstream directly (in spleen) or via lymph (elsewhere). Upon antigen encounter, lymphocytes are activated (primarily by antigen‐presenting dendritic cells) and proliferate within SLO. Effector T cells arising in SLO migrate to peripheral sites of inflammation: activated B cells differentiate into either memory B cells, which are thought to recirculate through SLO, or antibody‐secreting plasma cells, some of which lodge within the BM (long‐lived IgG‐producing cells), the spleen and medulla of lymph nodes (short‐lived IgG‐producing cells) and mucosal tissues (IgA‐producing cells). Long‐term protection (immunological memory) is provided by effector memory T cells, which patrol peripheral tissues; central memory T cells, which recirculate through SLO; and antibody‐secreting plasma cells. Here, primary lymphoid organs and SLO are italicized, while peripheral tissues appear in normal typeface. Trafficking routes of T cells, their progenitors and progeny are shown with black arrows: those of B cells, their progenitors and progeny are shown with gray arrows. (See page 8 in colour section at the back of the book)



Figure 2.

The multi‐step adhesion cascade and its essential molecular players. The top of this schematic diagram depicts the four distinct adhesion steps that leukocytes must undergo to accumulate in a blood vessel. Also shown are the predominant molecular determinants of each step on leukocytes (middle) and endothelial cells (bottom). A number of molecules can interact with more than one partner (symbolized by arrows). Leukocytes in the blood stream (arrows at left symbolize the laminar flow profile in microvessels) tether to endothelial cells and roll slowly downstream. Tethering is facilitated by leukocyte receptors that occur at high density on the tips of microvillous surface protrusions (L‐selectin, PSGL‐1, and α4 integrins), whereas subsequent rolling is not influenced by the topography of adhesion receptors. The most efficient tethering molecules are L‐ and P‐selectin. L‐selectin recognizes sulfated sialyl‐Lewisx‐like sugars (PNAd) in HEV and it also interact with other ligands on inflamed endothelial cells (not shown) and with PSGL‐1 on adherent leukocytes (broken arrow). PSGL‐1 binding to L‐ and P‐selectin requires decoration with sLex‐like sugar moieties in vicinity to an N‐terminal motif containing three tyrosines (Y) that must be sulfated. E‐selectin can also interact with PSGL‐1, but does not require sulfation and also recognizes other sLex‐bearing glycoconjugates. E‐selectin and the α4 integrins can tether some leukocytes, but their predominant function is to reduce rolling velocities. G‐protein‐coupled receptors, which uniformly feature seven transmembrane domains (7TMRs) on rolling cells can bind specific chemoattractants, such as a chemokine. This interaction provides an activating trasnmembrane signal that induces rapid activation of β2 and/or α4 integrins. The activated integrins then bind their ligands, members of the endothelial Ig superfamily. Note that α4 integrins can mediate activation‐independent rolling interactions as well as firm arrest. However, the latter function requires integrin activation (symbolized by the open conformation of the heterodimer).

Reprinted from Ref. 51. (See page 9 in colour section at the back of the book)


Figure 3.

Routes of lymphocyte trafficking through secondary lymphoid organs and other tissues. Antigen can first appear in the skin, mucosa, gut (alimentary tract), and blood. Lymphocyte recirculation through various secondary lymphoid organs gives them rapid access to antigen appearing by any of these means. The major routes of naïve and memory lymphocyte trafficking are shown. Here, secondary lymphoid organs are italicized, and other organs/tissues appear in regular typeface. Dark gray arrows represent travel through the circulation, while light gray arrows represent travel through lymphatics.

Reprinted from Scimone ML and von Andrian UH. Immunological homing and adhesion molecules. In Encyclopedia of Life Sciences. Chichester, UK: John Wiley and Sons Ltd., 2004. DOI: 10.1038/npg.els.0003990 (See page 9 in colour section at the back of the book)


Figure 4.

Lymph node anatomy, compartmentalization. and microcirculation. (A) as pointed out before, panel (A) appears to be corrupted. Background patterns are markedly distorted and different from the original Schematic drawing of a confocal micrograph of a murine inguinal LN. Major blood vessels, medulla, and cortex consisting of superficial B follicles (B) and the T‐cell area (T) containing high endothelial venules (HEV) are shown. (B) Confocal micrograph corresponding to the drawing in panel A. The microcirculation was visualized after i.v. injection of a mixture of green and red fluorescent dextrans. These plasma markers fill all microvessels. which appear yellow. The preparation is partly covered by fatty tissue, which diffracts fluorescent light emitted from the superficial epigastric vein resulting in a “bubbly” appearance. To identify the different lymphoid compartments, purified fluorescent B cells (gray) and T cells (dark gray) were injected i.v. 20h prior to this recording. After their entry into the LN via HEV, the homed cells segregate. B cells populate the more distal B follicles, whereas T cells remain in the paracortex. (C) A higher magnification of the boxed region in panel B illustrates the relationship of B and T cells and the microcirculation. (See page 10 in colour section at the back of the book)



Figure 5.

Schematic diagram of imprinting signals that direct primed T cells to the gut or skin. When naïve T cells are activated under the influence of retinoic acid (RA) they acquire a gut‐homing phenotype with high expression levels of the integrin α4β7 and the chemokine receptor CCR9. RA is produced by dendritic cells (DCs) in gut‐associated lymphoid tissues and also by intestinal epithelium and possibly by other sources. Simultaneously, RA suppresses T cell acquisition of skin‐homing molecules (E‐/P‐selectin ligands and CCR4). T‐cell activation in the absence of RA induces a preferential skin‐homing phenotype with high expression of E‐/P‐selectin ligands and CCR4. DC in skin‐draining peripheral lymph nodes (PLN DC) can generate additional specific imprinting signals, such as 1,25(OH)‐vitamin D3 and interleukin‐12, which together induce some T cells to express CCR10, a chemokine receptor that promotes T‐cell epidermotropism. Figure modified from Mora JR and von Andrian UH Retinoic acid: an educational “vitamin elixir” for gut‐seeking T cells. Immunity 21 (4): 458–460, 2004. (See page 10 in colour section at the back of the book)

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Article Title: Lymphocyte Trafficking
 

How to Cite

Avi N Kogan, Ulrich H von Andrian. Lymphocyte Trafficking. Compr Physiol 2011, Supplement 9: Handbook of Physiology, The Cardiovascular System, Microcirculation: 449-482. First published in print 2008. doi: 10.1002/cphy.cp020410