Lymphocyte Homing and the Structural Organisation of the Immune System

In an organised immune system cell migration needs to be directed. Tissue and microenvironment-selective lymphocyte homing is the basis for this organisation. The regulated expression of adhesion molecules and their ligands and of chemokines and their receptors underlie the structural and systemic organisations of the immune system, being essential for leukocyte development, lymphocyte recirculation, immune surveillance, and effector lymphocyte differentiation and targeting. In other words, tissue-specific homing is achieved by a sequence of overlapping steps with combinatorial diversity allowing for an "address" or "code" for leukocyte

Regulation of tissue-specific homing

Rolling: tissue-specific selectins/ligands tissue-specific integrins/ligands

Regulation of tissue-specific homing

Rolling: tissue-specific selectins/ligands tissue-specific integrins/ligands

Activation/adhesion: tissue-specific chemokines/ligands • • tissue-specific integrins/ligands

Activation/adhesion: tissue-specific chemokines/ligands • • tissue-specific integrins/ligands

Homing to lymph nodes

Rolling: GlyCAM-1 (PNAd)/L selectin

Homing to lymph nodes

Rolling: GlyCAM-1 (PNAd)/L selectin

Activation/adhesion: CCR7/SLC

Activation/adhesion: CCR7/SLC

Homing to the skin

Rolling: CLA/E selectin

Homing to the skin

Rolling: CLA/E selectin

Activation/adhesion: CCR4/TARC

Activation/adhesion: CCR4/TARC

Homing to the gut

\ >

l Rolling: a4ß7/MAdCAM-1

Wi

——^ Activation/adhesion: XXP9/TEXK

ajyMAdCAM-1

Fig. 3. Tissue-specific T cell homing. Post-capillary venules in different tissues and microenvironments express unique combinations of adhesion molecules and chemokines involved in the recruitment of lymphocytes that express the appropriate counter receptor (A). (B-D) A schematic representation of the molecular interactions mediating T cell migration to lymph nodes, skin and gut, respectively, is provided.

migration (Fig. 3). In this section, we refer to the T cell homing patterns as a reproducible scenario for the regulation of tissue localisation of other migrating cells.

T cells originate from bone marrow precursors that mature into naive T cells in the thymus. Naive T cells traffic to secondary lymphatic organs, including peripheral lymph nodes, Peyer's patches, mesenteric lymph nodes and the spleen, where they might encounter antigen and become polarised into T helper 1 (TH1), TH2 and other effector T cells, which are collected in efferent lymphatics and then enter the circulation via the thoracic duct. Activated T cells traffic to extralymphoid organs, including the non-inflamed lungs, skin, central nervous system and gastrointestinal organs. Many activated T cells ultimately migrate to the liver to undergo apoptosis. Activated T cells can home to almost all inflamed organs and tissues.

Post-capillary venules in different tissues and microenvironments express unique combinations of adhesion molecules and chemokines involved in the recruitment of lymphocytes that express the appropriate counter receptor.20

For example, expression of L-selectin by naive T lymphocytes is required for migration through high endothelial venules (expressing its counter-receptor GlyCAM-1) and access to the lymph node parenchyma. Interaction of E-selectin (expressed by inflamed skin endothelium) with its ligand CLA directs T lymphocytes to migrate into the skin. Similarly, LFA1-ICAM interactions mediate lymphocyte trafficking to peripheral lymph nodes and attachment to APCs, whereas the a4^7-integrin-MADCAM1 and VLA-4-VCAM1 interactions have central roles in lymphocyte migration to mucosal lymphoid organs and inflamed tissues, respectively.20

Chemokines and their receptors are leading molecules in the regulation of lymphocyte homing. Once displayed on the endothelial surface chemokines can trigger integrin activation leading to leukocyte arrest on the endothelial wall.21

Chemokines and their receptors play a key role in programming migrations during lymphocyte development. The response of pro-thymocytes in murine foetal blood to CXCL12 and CCL25 (TECK, thymus expressed chemokine) suggests that they are involved, with their receptors CXCR4 and CCR9, in the colonisation of the thymus.22 Once CD4 and CD8 singlepositive populations of thymocytes have developed, they acquire the expression of the chemokine receptor CCR7 before exiting the thymus.23 This receptor is important for the exit from the thymus, and also for T cell localisation to secondary lymphoid tissues. Its receptor CCL19 (ELC) is expressed by venular endothelial cells in the thymic medulla, suggesting that it favours T cell emigration.24

After the development of lymphocyte in the thymus, lymphocyte migration and activation in secondary lymphoid tissues are regulated by the CCR7 ligands, CCL19 and CCL21 (SLC). Lymphocytes are targeted in the T cell areas of the lymph node by specific chemokines such as CCL21 and CXCL12, whereas migration to B cell follicles depends on CXCL13.25

Once naive T cells are activated by antigen encounter, they undergo reprogramming of their homing properties during proliferation, which enables them to retain a "memory" of the site of activation and their target tissue. The induction of differential homing properties is probably determined by the tissue-derived factors that reach the tissue-draining lymph nodes.26'27 For example, T cells responding to an antigen in the intestine-associated lymphoid tissue up-regulate the intestine homing receptor a4fi7 and respond to the intestinal chemokine CCL2527 (Fig. 3). Similarly, the population of skin-homing lymphocytes expressing CLA as homing receptor responds to the CCL17 (TARC) chemokine, which is produced by the parenchymal components in the skin.28

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment