T cell responses are initiated primarily in secondary lymphoid organs, and the effector phase occurs mainly in peripheral tissue sites of infection . Thus, T cells at different stages of their lives have to migrate in different ways:

• Naive T cells must migrate between blood and secondary (peripheral) lymphoid organs throughout the body, until they encounter dendritic cells within the lymphoid organ that display the antigens the T cells recognize .

• After the naive T cells are activated and differentiate into effector cells, these cells must migrate back to the sites of infection, where they function to kill microbes.

The migration of naive and effector T cells is controlled by three families of proteins—selectins, integrins, and chemokines—that regulate the migration of all leukocytes. The routes of migration of naive and effector T cells differ significantly because of selective expression of different adhesion molecules and chemokine receptors on naive T cells versus effector T cells, together with the selective expression of endothelial adhesion molecules and chemokines in lymphoid tissues and sites of inflammation (Fig. 1).

Fig1. Migration of naive and effector T lymphocytes.

Naive T cells express the adhesion molecule L-selectin (CD62L) and the chemokine receptor CCR7, which mediate the selective migration of the naive cells into lymph nodes through specialized blood vessels called high endothelial venules (HEVs) (see Fig. 1). HEVs are located in the T cell zones of lymphoid tissues and are lined by specialized endothelial cells, which express carbohydrate ligands that bind to L-selectin. HEVs also display chemokines that are made only in lymphoid tissues and are specifically recognized by CCR7. The migration of naive T cells proceeds in a multistep sequence like that of migration of all leukocytes through blood vessel:

• Naive T cells in the blood engage in L-selectin– mediated rolling interactions with the HEV, allowing chemokines to bind to CCR7 on the T cells.

 • CCR7 transduces intracellular signals that activate the integrin LFA-1 on the naive T cell, increasing the binding affinity of the integrin.

 • The increased affinity of the integrin for its ligand, ICAM-1, on the HEV results in firm adhesion and arrest of the rolling T cells.

• The T cells then exit the vessel through the endothelial junctions and are retained in the T cell zone of the lymph node because of the chemokines produced there. Thus, many naive T cells that are carried by the blood into an HEV migrate to the T cell zone of the lymph node stroma. This happens constantly in all lymph nodes and mucosal lymphoid tissues in the body. Effector T cells do not express CCR7 or L-selectin, and thus they are not drawn into lymph nodes.

The phospholipid sphingosine 1-phosphate (S1P) plays a key role in the egress of T cells from lymph nodes. The levels of S1P are higher in the blood and lymph than inside lymph nodes. S1P binds to and induces internalization of its receptor, which keeps the expression of the receptor on circulating naive T cells low. When a naive T cell enters the node, it is exposed to lower concentrations of S1P, and expression of the receptor begins to increase. If the T cell does not recognize any antigen, the cell leaves the node through efferent lymphatic vessels, following the gradient of S1P into the lymph. If the T cell does encounter specific antigen and is activated, the surface expression of the S1P receptor is suppressed for several days by CD69, which is transiently expressed following T cell activation. As a result, recently activated T cells stay in the lymph node long enough to undergo clonal expansion and differentiation. When this process is completed, S1P receptor is reexpressed on the cell surface; at the same time, the cells lose expression of L-selectin and CCR7, which previously attracted the naive T cells to the lymph nodes. Therefore, activated T cells are drawn out of the nodes into the draining lymph, which then transports the cells to the circulation. The net result of these changes is that differentiated effector T cells leave the lymph nodes and enter the circulation. The importance of the S1P pathway has been highlighted by the development of a drug (fingolimod) that binds to the S1P receptor and blocks the exit of T cells from lymph nodes. This drug is approved for the treatment of the inflammatory disease multiple sclerosis.

Effector T cells migrate to sites of infection because they express adhesion molecules and chemokine receptors that bind to ligands expressed or displayed on vascular endothelium at sites of infection. The process of differentiation of naive T lymphocytes into effector cells is accompanied by changes in the types of adhesion molecules and chemokine receptors expressed on these cells (see Fig1). The migration of activated T cells into peripheral tissues is controlled by the same kinds of interactions involved in the migration of other leukocytes into tissues :

• Activated T cells express high levels of the glycoprotein ligands for E- and P-selectins and the integrins LFA-1 and VLA-4 (very late antigen 4). Innate immune cytokines produced in response to the infection, such as TNF and IL-1, act on the endothelial cells to increase expression of E- and P-selectins, as well as ligands for integrins, especially ICAM-1 and vascular cell adhesion molecule 1 (VCAM-1), the ligand for the VLA-4 integrin.

• Effector T cells that are passing through the blood vessels at the infection site bind first to the endothelial selectins, leading to rolling interactions.

 • Effector T cells also express receptors for chemokines that are produced by macrophages and endothelial cells at these inflammatory sites and are displayed on the surface of the endothelium. The rolling T cells bind these chemokines, leading to increased affinity of the integrins for their ligands and firm adhesion of the T cells to the endothelium.

• After the effector T lymphocytes are arrested on the endothelium, they engage other adhesion molecules at the junctions between endothelial cells, crawling through these junctions into the tissue. Chemokines that were produced by macrophages and other cells in the tis sues stimulate the motility of the transmigrating T cells.

The net result of these molecular interactions between the T cells and endothelial cells is that the T cells migrate out of the blood vessels to the area of infection. Naive T cells do not express ligands for E- or P-selectin and do not express receptors for chemokines produced at inflammatory sites. Therefore, naive T cells do not migrate into sites of infection or tissue injury.

The homing of effector T cells to an infected tissue is independent of antigen recognition, but lymphocytes that recognize antigens are preferentially retained and activated at the site. The homing of effector T cells to sites of infection mainly depends on adhesion molecules and chemokines. Therefore, any effector T cell present in the blood, regardless of antigen specificity, can enter the site of any infection. This nonselective migration presumably maximizes the chances of effector lymphocytes entering tissues where they may encounter the microbes they recognize. The effector T cells that leave the circulation and that specifically recognize microbial antigen presented by local tissue APCs become reactivated and contribute to the killing of the microbe in the APC. One consequence of this reactivation is an increase in the expression of VLA integrins on the T cells. Some of these integrins specifically bind to molecules present in the extracellular matrix, such as hyaluronic acid and fibronectin. Therefore, the antigen-stimulated lymphocytes adhere firmly to the tissue matrix proteins near the antigen, which may serve to keep the cells at the inflammatory sites. This selective retention contributes to accumulation of more and more T cells specific for microbial antigens in the region of the infection.

As a result of this sequence of T cell migration events, the effector phase of T cell–mediated immune responses may occur at any site of infection. Whereas the activation of naive T cells requires antigen presentation and costimulation by dendritic cells, differentiated effector cells are less dependent on costimulation. Therefore, the proliferation and differentiation of naive T cells are con fined to lymphoid organs, where dendritic cells (which express abundant costimulators) display antigens, but the functions of effector T cells may be reactivated by any host cell displaying microbial peptides bound to MHC molecules, not just dendritic cells.

Elucidation of the molecular interactions involved in leukocyte migration has spurred many attempts to develop agents to block the process of cell migration into tissues. Antibodies against integrins are effective in the inflammatory diseases multiple sclerosis and inflammatory bowel disease. The clinical utility of these drugs is limited by the increased risk of new infection or reactivation of latent infections, because the immune surveillance function of the T cells is impaired when their migration into tissues is blocked. A small-molecule inhibitor of the S1P pathway is used for treating multiple sclerosis, as mentioned previously. Small molecules that bind to and block chemokine receptors have also been developed, and some have shown efficacy in inflammatory bowel disease.