Integrins are cell surface proteins that mediate adhesion of cells to other cells or to extracellular matrix, through specific binding interactions with various ligands. There are 24 different mammalian integrins, all of which are heterodimers containing 1 of 18 types of α chains and 1 of 8 types of β chains. The extracellular globular heads of both chains contribute to ligand binding. The cytoplasmic domains of the integrins interact with cytoskeletal components (including vinculin, talin, actin, α-actinin, and tropomyosin). The name integrin for this family of proteins derives from the idea that these proteins integrate signals triggered by extracellular ligands with cytoskeleton-dependent motility, shape change, and phagocytic responses. Although we will focus on the leukocyte adhesive functions of integrins, these molecules have many other biological functions, including adhesion, proliferation, differentiation of epithelial cells, and platelet adhesion and aggregation during blood coagulation. Inflammatory cytokines and other signals increase endothelial expression of integrin ligands and binding affinity of leukocyte integrins, thus promoting leukocyte adhesion to endothelium at sites of inflammation.

In the immune system, two important integrins that are expressed on myeloid cells and lymphocytes are leukocyte function–associated antigen 1 (LFA-1), more precisely named αL β2 or CD11aCD18, and very late antigen 4 (VLA-4), also named α4 β1 or CD49dCD29 (see Table 1). One important ligand for LFA-1 is intercellular adhesion molecule 1 (ICAM-1, CD54), a membrane glycoprotein expressed on cytokine-activated endo thelial cells and on a variety of other cell types, including lymphocytes, DCs, macrophages, fibroblasts, and most epithelial cells. The extracellular portion of ICAM-1 is composed of globular domains, called immunoglobulin (Ig) domains, which share sequence homology and structural features with domains found in Ig molecules. Many proteins in the immune system contain Ig domains and belong to the Ig superfamily (see Chapter 5). LFA-1 binding to ICAM-1 is important for leukocyte-endothelial interactions (discussed later) and T-cell interactions with antigen-presenting cells (APCs) (see Chapter 9). 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. Other integrins also play roles in innate and adaptive immune responses. For example, MAC-1 (αM β2 , CD11bCD18, or complement receptor 3 [CR3]) on circulating monocytes binds to ICAM-1 and mediates adhesion to endothelium. MAC-1 also functions as a complement receptor, as does another integrin of the β2 family known as CD11cCD18 (αX β2 , complement receptor 4 [CR4]); both MAC-1 and CD11cCD18 bind particles opsonized with a product of complement activation called the inactivated C3b (iC3b) fragment (discussed in Chapters 4 and 13), and thereby enhance phagocytosis of microbes. CD11cCD18 is expressed mainly on DCs but also on other myeloid cells and activated B cells. It helps DCs ingest apoptotic cells. The integrin α4 β7 is expressed on lymphocytes that home to intestinal mucosa and binds to an endothelial protein called mucosal addressin cell adhesion molecule 1 (MAdCAM-1). αE β7 (CD103) is an integrin that binds to an epithelial adhesion molecule called E-cadherin. αE β7 is expressed on subsets of T cells and DCs that are found within epithelial layers of skin and mucosa.

Table1. Major Leukocyte-Endothelial Adhesion Molecules

Integrins rapidly increase the affinity for their ligands in response to intracellular signals, which are induced in all leukocytes by chemokine binding to chemokine receptors and in T cells by antigen binding to antigen receptors. Chemokine receptor and antigen receptor engagement trigger signaling pathways that lead to the association of RAP family small GTPase proteins and cytoskeleton-interacting proteins with the cytoplasmic tails of the integrin proteins. This results in conformational changes in the extracellular domains of the integrins that lead to increased affinity (Fig. 1). In the low-affinity state, the stalks of the extracellular domains of each integrin subunit are bent over and the ligand-binding globular heads are close to the plasma membrane. In response to alterations in the cytoplasmic tail induced by chemokines or antigens, the stalks extend, bringing the globular heads away from the membrane to a position where they more effectively interact with their ligands. The process by which intracellular signals, generated in response to chemokines or antigens, alter the binding functions of the extracellular domain of integrins is called inside-out signaling.

Fig1. Integrin activation. (A) The integrins on blood leukocytes are normally in a low-affinity state. If a leukocyte comes close to endothelial cells, such as when selectin-dependent rolling of leukocytes occurs, then chemokines displayed on the endothelial surface can bind chemokine receptors on the leukocyte. Chemokine receptor signaling then occurs, which activates the leukocyte integrins, increasing their affinity for their ligands on the endothelial cells. (B) Ribbon diagrams are shown of bent and extended conformations of a leukocyte integrin, corresponding to low- and high-affinity states, respectively. The α chain is red and the β chain is blue. ICAM-1, Intercellular adhesion molecule 1. B, From Takagi J, Springer TA. Integrin activation and structural rearrangement. Immunol Rev. 2002;186:141–163.

Chemokines also induce clustering of integrins on leukocyte surfaces. This results in a higher local concentration of integrins at the sites of interaction with endothelial cells, where the chemokines are displayed, leading to increased overall strength (avidity) of integrin-mediated leukocyte binding to the endothelium, which promotes the migration of leukocytes into tissues.

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