1

CXCR3 \r7 CCR5

E- or P-selectin

CXCL10 (others) CCL4 (others)

ICAM-1 or VCAM-1

Initial weak adhesion of effector and memory T cells to cytokine activated endothelium at peripheral site of infection

Activation of integrins and chemokinesis

Activation of integrins and chemokinesis

Stable arrest on cytokine activated endothelium at peripheral site of infection

FIGURE 3-6 Migration of naive and effector T lymphocytes. A, Naive T lymphocytes home to lymph nodes as a result of L-selectin binding to its ligand on high endothelial venules, which are present only in lymph nodes, and as a result of binding chemokines (CCL19 and CCL21) displayed on the surface of the high endothelial venule. Activated T lymphocytes, including effector cells, home to sites of infection in peripheral tissues, and this migration is mediated by E-selectin and P-selectin, integrins, and chemokines that are produced at sites of infection. Additional chemokines and chemokine receptors, besides the ones shown, are involved in effector/memory T cell migration. B, The adhesion molecules, chemokines, and chemokine receptors involved in naive and effector/memory T cell migration are described.

a molecule called MadCAM-1 (mucosal addressin cell adhesion molecule 1).

• The subsequent firm adhesion of the T cells to the HEVs is mediated by integrins, mainly LFA-1. The affinity of these integrins on naive T cells is rapidly increased by CCL19 and CCL21, which we introduced in Chapter 2 as chemokines required for the maintenance of T cell zones in lymph nodes. CCL19 is con-stitutively produced by HEVs and is bound to glycosaminoglycans on the cell surface for display to rolling lymphocytes. CCL21 is produced by other cell types in the lymph node and is displayed by HEVs in the same fashion as CCL19. Recall that both these chemokines bind to the chemokine receptor called CCR7, which is highly expressed on naive lymphocytes. This interaction of the chemokines with CCR7 ensures that naive T cells increase integrin avidity and are able to adhere firmly to HEVs.

• The firmly adherent T cells are no longer subject to dislodgment by the blood flow, but they are capable of crawling on the endothelial surfaces toward intercellular junctions. At these junctions, the T cells move through the vessel wall into the extravascular tissue. This process is likely dependent on other adhesion molecules on the T cell binding to HEV adhesion molecules whose expression is restricted to intercellular junctions.

The important role for L-selectin and chemokines in naive T cell homing to secondary lymphoid tissues is supported by many different experimental observations. Lymphocytes from L-selectin knockout mice do not bind to peripheral lymph node HEVs, and the mice have a marked reduction in the number of lymphocytes in peripheral lymph nodes. There are very few naive T cells in the lymph nodes of mice with genetic deficiencies in CCL19 and CCL21, or CCR7, but the B cell content of these lymph nodes is relatively normal.

Exit of Naive T Cells from Lymph Nodes

Naive T cells that have homed into lymph nodes but fail to recognize antigen and to become activated will eventually return to the blood stream. This return to the blood completes one recirculation loop and provides the naive T cells another chance to enter secondary lym-phoid tissues and search for the antigens they can recognize. The major route of reentry into the blood is through the efferent lymphatics, perhaps via other lymph nodes in the same chain, and then through the lymphatic vasculature to the thoracic or right lymphatic duct, and finally into the superior vena cava or right subclavian vein.

The exit of naive T cells from lymph nodes is dependent on a lipid chemoattractant called sphingosine 1-phosphate (S1P), which binds to a signaling receptor on T cells called sphingosine 1-phosphate receptor 1 (S1PR1) (Fig. 3-7). S1P is present at relatively high concentrations in the blood and lymph compared with tissues. This concentration gradient is maintained because an SIP-degrading enzyme, S1P lyase, is ubiquitously present in tissues, so the tissue concentration of the lipid is less than in the lymph and blood. S1PR1 is a G protein-coupled receptor.

Signals generated by S1P binding to S1PR1 stimulate directed movement of the naive T cells along the S1P concentration gradient out of the lymph node parenchyma. Circulating naive T cells have very little surface S1PR1 because the high blood concentration of S1P causes internalization of the receptor. Once a naive T cell enters a lymph node, where S1P concentrations are low, it may take several hours for the surface S1P1R to be re-expressed. This allows time for a naive T cell to interact with antigen-presenting cells before it is directed down the S1P concentration gradient into the efferent lymphatic. S1P and the S1P1R are also required for mature naive T cell egress from the thymus, migration of activated T cells out of lymph nodes, and migration of antibody-secreting B cells from secondary lymphoid organs.

Our understanding of the role of S1P and S1PR1 in T cell trafficking is based in large part on studies of the effects of a drug called fingolimod (FTY720), which binds to S1P1R and causes its down-modulation from the cell surface. Fingolimod blocks T cell egress from lymphoid organs and thereby acts as an immunosuppressive drug. It is now approved for the treatment of multiple sclerosis, an autoimmune disease of the central nervous system, and there is great interest in use of fingolimod and other drugs with a similar mechanism of action to treat various autoimmune diseases or graft rejection. Additional experimental evidence for the central role of S1P in naive T cell trafficking comes from studies of mice with genetic ablation of S1PR1. In these mice, there is failure of T cells to leave the thymus and populate secondary lymphoid organs. If naive T cells from S1PR1 knockout are injected into the circulation of other mice, the cells enter lymph nodes but are unable to exit.

Recirculation of T Cells through Other Lymphoid Tissues

Naive T cell homing into gut-associated lymphoid tissues, including Peyer's patches and mesenteric lymph nodes, is fundamentally similar to homing to other lymph nodes and relies on interactions of the T cells with HEVs, which are mediated by selectins, integrins, and chemokines. One particular feature of naive T cell homing to mesen-teric lymph nodes and Peyer's patches is the contribution of an Ig superfamily molecule called MadCAM-1 (mucosal addressin cell adhesion molecule 1), which is expressed on HEVs in these sites but not typically elsewhere in the body. Naive T cells express two ligands that bind to MadCAM-1, L-selectin and an integrin called a4p7, and both contribute to the rolling step of naive T cell homing into gut-associated lymphoid tissues.

Naive T cell migration into the spleen is not as finely regulated as homing into lymph nodes. The spleen does not contain HEVs, and it appears that naive T cells are delivered to the marginal zone and red pulp sinuses by passive mechanisms that do not involve selectins, integ-rins, or chemokines. However, CCR7-binding chemo-kines do participate in directing the naive T cells into the white pulp. Even though homing of naive T cells to the spleen appears to be less tightly regulated than homing into lymph nodes, the rate of lymphocyte passage through

Recently arrived naive T cell, or recently activated T cell: low S1PR1

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