a4ß7 (CD49dCD29)

Monocytes, T cells (gut homing, naive, effector, memory)

VCAM-1 (CD106), MadCAM-1; endothelium in gut and gut-associated lymphoid tissues

CLA-1, cutaneous lymphocyte antigen 1; GlyCAM-1, glycan-bearing cell adhesion molecule 1; HEV, high endothelial venule; ICAM-1, intracellular adhesion molecule 1; IL-1, interleukin-1; LFA-1, leukocyte function-associated antigen 1; MadCAM-1, mucosal addressin cell adhesion molecule 1; PNAd, peripheral node addressin; PSGL-1, P-selectin glycoprotein ligand 1; TNF, tumor necrosis factor; VCAM-1, vascular cell adhesion molecule 1; VLA-4, very late antigen 4.

molecules may display the carbohydrate ligands for E-selectin, including the glycoproteins PSGL-1 and E-selectin ligand 1 and some glycolipids.

A third selectin, called L-selectin (CD62L), is expressed on leukocytes but not on endothelial cells. The ligands for L-selectin are sialomucins displayed on high endothelial venules, collectively called peripheral node addressin (PNAd). A major recognition determinant that L-selectin binds to on these sialomucins is sialyl 6-sulfo Lewis X. The expression of these ligands is increased by cytokine activation of endothelial cells. L-selectin on neutrophils serves to bind these cells to endothelial cells that are activated by IL-1, TNF, and other cytokines produced at sites of inflammation. In adaptive immunity, L-selectin is important for naive T lymphocytes to home into lymph nodes through high endothelial venules. Leukocytes express L-selectin and the carbohydrate ligands for P-selectin and E-selectin at the tips of their microvilli, facilitating interactions with molecules on the endothe-lial cell surface.

Integrins and Integrin Ligands

Integrins are heterodimeric cell surface proteins composed of two noncovalently linked polypeptide chains that mediate adhesion of cells to other cells or to extracellular matrix, through specific binding interactions with various ligands. There are more than 30 different integrins, all with the same basic structure, containing one of more than 15 types of a chains and one of seven types of P chains. The extracellular globular heads of both chains contribute to interchain linking and to divalent cation-dependent ligand binding. The cytoplasmic domains of the integrins interact with cytoskeletal components (including vinculin, talin, actin, a-actinin, and tropo-myosin). The name of this family of proteins derives from the idea that they coordinate (i.e., integrate) signals generated when they bind extracellular ligands with cytoskeleton-dependent motility, shape change, and phagocytic responses.

In the immune system, the most important integrins are two that are expressed on leukocytes, called LFA-1 (leukocyte function-associated antigen 1, more precisely named p2aL or CD11aCD18) and VLA-4 (very late antigen 4, or Pja4, or CD49dCD29) (see Table 3-1). One important ligand for LFA-1 is intercellular adhesion molecule 1 (ICAM-1, CD54), a membrane glycoprotein expressed on cytokine-activated endothelial cells and on a variety of other cell types, including lymphocytes, dendritic cells, macrophages, fibroblasts, and keratinocytes. The extracellular portion of ICAM-1 is composed of globular domains that share some sequence homology and tertiary structural features of domains found in immuno-globulin (Ig) molecules and are called Ig domains. (Many proteins in the immune system contain Ig domains and belong to the Ig superfamily, which is discussed in more detail in Chapter 5.) LFA-1 binding to ICAM-1 is important for leukocyte-endothelial interactions (discussed later) and T cell interactions with antigen-presenting cells (see Chapter 6). Two other Ig superfamily ligands for LFA-1 are ICAM-2, which is expressed on endothelial cells, and ICAM-3, which is expressed on lymphocytes.

VLA-4 binds to vascular cell adhesion molecule 1 (VCAM-1, CD106), an Ig superfamily protein expressed on cytokine-activated endothelial cells in some tissues, and this interaction is important for leukocyte recruitment into inflammatory sites. Other integrins also play roles in innate and adaptive immune responses. For example, Mac-1 (P2am, CD11bCD18) on circulating monocytes binds to ICAM-1 and mediates adhesion to endothelium. Mac-1 also functions as a complement receptor, binding particles opsonized with a product of complement activation called the inactivated C3b (iC3b) fragment, and thereby enhances phagocytosis of microbes.

An important feature of integrins is their ability to respond to intracellular signals by rapidly increasing their affinity for their ligands (Fig. 3-2). This is referred to as activation and occurs in response to signals generated from chemokine binding to chemokine receptors and in lymphocytes by intracellular signals generated when antigen binds to antigen receptors. The process of changes in the binding functions of the extracellular domain of integrins induced by intracellular signals is called inside-out signaling. Chemokine- and antigen

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