At least five members of the immunoglobulin superfamily are especially important in T-cell activation (Fig. 9.9). Three very similar intercellular adhesion molecules (ICAMs)—ICAM-1, ICAM-2, and ICAM-3—all bind to the T-cell integrin LFA-1. ICAM-1 and ICAM-2 are expressed on endothelium as well as on antigen-presenting cells, and binding to these molecules enables lymphocytes to migrate through blood vessel walls. ICAM-3 is expressed only on naive T cells and is thought to have an important role in the adhesion of T cells to antigen-presenting cells by binding to LFA-1 expressed on dendritic cells. The two remaining immunoglobulin superfamily adhesion molecules, CD58 (formerly known as LFA-3) on the antigen-presenting cell and CD2 on the T cell, bind to each other; this interaction synergizes with that of ICAM-1 or ICAM-2 with LFA-1.
As discussed above in the context of lymphoid tissue development (see Section 9-3), naive T cells are specifically attracted into the T-cell zones of secondary lymphoid tissues by chemokines. The chemokines bind to proteoglycans in the extracellular matrix and high endothelial venule wall, forming a chemical gradient, and are recognized by receptors on the naive T cell. The extravasation of naive T cells is prompted by the chemokine CCL21, which is expressed by vascular high endothelial cells and the stromal cells of lymphoid tissues, as well as by dendritic cells that reside in T-cell zones. It binds to the chemokine receptor CCR7 on naive T cells, stimulating activation of the intracellular receptor-associated G-protein subunit Gαi. The resulting intracellular signaling rapidly increases the affinity of integrin binding (see Section 3-18).
Fig. 9.10 Lymphocytes in the blood enter lymphoid tissue by to the activation of LFa-1. This causes the T cell to bind tightly crossing the walls of high endothelial venules. The first step is to ICaM-1 on the endothelial cell, allowing migration across the the binding of L-selectin on the lymphocyte to sulfated carbohydrates endothelium. as in the case of neutrophil migration (see Fig. 3.31), (sulfated sialyl-LewisX) of GlyCaM-1 and Cd34 on the hev. Local matrix metalloproteinases on the lymphocyte surface (not shown) chemokines such as CCL21 bound to a proteoglycan matrix on the enable the lymphocyte to penetrate the basement membrane. hev surface stimulate chemokine receptors on the T cell, leading
The entry of a naive T cell into a lymph node is shown in detail in Fig. 9.10. Initial rolling of the T cell along the surface of HEVs is mediated by L-selectin. Recognition of CCL21 on the endothelial surface of the HEV by CCR7 on the T cell causes LFA-1 to become activated, increasing its affinity for ICAM-2 and ICAM-1. ICAM-2 is expressed constitutively on all endothelial cells, whereas in the absence of inflammation, ICAM-1 is expressed only on the high endothelial cells of secondary lymphoid tissues. The organization of LFA-1 molecules in the T-cell membrane is also altered by chemokine stimulation, such that they become concentrated in areas of cell–cell contact. This produces stronger binding, which arrests the T cell on the endothelial surface and thus enables it to enter the lymphoid tissue.