Beta2-Integrins and Interacting Proteins in Leukocyte Trafficking, Immune Suppression, and Immunodeficiency Disease

Abstract

Beta2-integrins are complex leukocyte-specific adhesion molecules that are essential for leukocyte (e.g., neutrophil, lymphocyte) trafficking, as well as for other immunological processes such as neutrophil phagocytosis and ROS production, and T cell activation. Intriguingly, however, they have also been found to negatively regulate cytokine responses, maturation, and migratory responses in myeloid cells such as macrophages and dendritic cells, revealing new, and unexpected roles of these molecules in immunity. Because of their essential role in leukocyte function, a lack of expression or function of beta2-integrins causes rare immunodeficiency syndromes, Leukocyte adhesion deficiency type I, and type III (LAD-I and LAD-III). LAD-I is caused by reduced or lost expression of beta2-integrins, whilst in LAD-III, beta2-integrins are expressed but dysfunctional because a major integrin cytoplasmic regulator, kindlin-3, is mutated. Interestingly, some LAD-related phenotypes such as periodontitis have recently been shown to be due to an uncontrolled inflammatory response rather than to an uncontrolled infection, as was previously thought. This review will focus on the recent advances concerning the regulation and functions of beta2-integrins in leukocyte trafficking, immune suppression, and immune deficiency disease.

Keywords: integrin; kindlin-3; leukocyte adhesion cascade; leukocyte adhesion deficiency; trafficking.

Figure 1

The main roles of beta2-integrins in immune activation and suppression. (A) phagocytosis. Beta2-integrins mediate phagocytosis by binding to iC3b on the surface of complement-coated bacteria. (B) regulation of T cell activation by a dendritic cell. Beta2-integrins participate in the formation of an immunological synapse between a T cell and an antigen presenting cell such as DC. The synapse stabilizes the interaction between and regulates signaling in the two participating cells. (C) target cell killing. Beta2-integrins participate in forming and maintaining an immunological synapse between a cytotoxic T cell and an infected cell. (D) leukocyte recruitment to tissues. Leukocytes are activated by selectins and chemokines on the surface of activated endothelial cells close to a site of inflammation. This slows down the leukocyte speed and induces integrins to change their conformation through inside-out signaling, allowing them to bind ICAMs on the endothelium. Beta2-integrins are essential in the slow rolling and firm adhesion of a leukocyte, after which the cells transmigrate to the inflamed tissue. Leukocytes use the chemokine gradient to navigate toward the site of inflammation. (E) regulation of TLR-signaling. Beta2-integrin CD11b/CD18 restrains macrophage activation and cytokine production upon TLR (Toll-like receptor) activation by LPS (lipopolysaccharide). (F) restriction of dendritic cell migration, maturation, and Th1 priming. Proper beta2-integrin—cytoskeleton linkage controls DC maturation toward a migratory phenotype and restricts priming of Th1 cells. (G) restriction of B cell receptor signaling. Interaction of CD11b/CD18 and CD22 on the surface of an autoreactive B cell leads to constraint in BCR signaling. This decreases auto-reactive B cell proliferation and antibody production.