Once naive T cells have arrived in the T-cell zone via high endothelial venules, CCR7 directs their retention in this location, as they are attracted to dendritic cells that produce CCL21 and CCL19 in the T-cell zone. The naive T cells scan the surfaces of dendritic cells for specific peptide:MHC complexes, and if they find their antigen and bind to it, they are trapped in the lymph node. If they are not activated by antigen, naive T cells soon leave the lymph node (see Fig. 9.4).
9-7 The exit of T cells from lymph nodes is controlled by a chemotactic lipid.
T cells exit from a lymph node via the cortical sinuses, which lead into the medullary sinus and then the efferent lymphatic vessel. The egress of T cells from secondary lymphoid organs involves the lipid molecule sphingosine 1-phosphate (S1P) (Fig. 9.11). This lipid has chemotactic activity and signaling properties similar to those of chemokines, in that the receptors for S1P are G-protein-coupled receptors. A concentration gradient of S1P between the lymphoid tissues and lymph or blood acts to draw unactivated naive T cells expressing an S1P receptor away from the lymphoid tissues and back into circulation.
Fig. 9.11 The egress of lymphocytes from lymphoid tissue is mediated by a sphingosine 1-phosphate (S1P) gradient. The level of sphingosine 1-phosphate (s1p) within lymphoid tissue is low compared with efferent lymph, thereby forming an s1p gradient (indicated by shading). The s1p receptor 1 (s1pr1) expressed on naive T cells is responsive to the s1p gradient. In the absence of antigen recognition, s1pr1 signaling promotes T-cell egress from the T-cell zones into the efferent lymphatic vessel. T cells activated by an antigen-expressing dendritic cell upregulate Cd69, which causes a decrease in s1pr1 expression and retention in the T-cell zone. effector T cells eventually reexpress s1pr1 as Cd69 expression decreases, and thereby egress from the lymph node. FTY720 inhibits T-cell egression by downmodulating expression of s1pr1 by ligand-induced internalization and by s1pr1-mediated closure of egress ports on the endothelium by enhancement of junctional contacts (not shown).
T cells activated by antigen in lymphoid organs downregulate the surface expression of the S1P receptor, S1PR1, for several days. This loss of S1PR1 surface expression is caused by CD69, a surface protein whose expression is induced by T-cell receptor signaling and which acts to internalize S1PR1. During this period, T cells cannot respond to the S1P gradient and do not exit the lymphoid organ. After several days of proliferation, as T-cell activation wanes, CD69 expression decreases and S1PR1 reappears on the surface of effector T cells, allowing them to migrate out of the lymphoid tissue in response to the S1P gradient.