Rheostat regulation of integrin-mediated leukocyte adhesion
Ivor S. Douglas, Themistocles Dassopoulos
Ivor S. Douglas, Themistocles Dassopoulos
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Commentary

Rheostat regulation of integrin-mediated leukocyte adhesion

Abstract

The homing of activated T lymphocytes to the gut in inflammatory bowel diseases is dependent on their coordinated, integrin-mediated adhesion and de-adhesion to substrates and blood vessel walls. In this issue of the JCI, Park and colleagues reveal a key modulatory role of a binding site within β integrins, known as the ADMIDAS domain, in controlling integrin de-adhesion in mice (see the related article beginning on page 2526). These observations add to our growing understanding of how integrin adhesiveness is regulated and raise the notion of the existence of a biological rheostat for lymphocyte homing. Disturbed migratory rheostat tone could account for variations in interindividual immune responses observed in patients with inflammatory bowel disease or other lymphocyte-mediated inflammatory disorders. These findings will inform future strategies to design small molecules for the treatment of a spectrum of chronic inflammatory conditions.

Authors

Ivor S. Douglas, Themistocles Dassopoulos

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Figure 2

Gut-targeted homing of α4β7+ naive and effector T cells.

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Gut-targeted homing of α4β7+ naive and effector T cells. ...
The gut-associated lymphoid tissues consist of (A) inductive sites, including secondary lymphoid organs, organized lymphoid tissues such as Peyer’s patches, and mesenteric lymph nodes that are responsible for the inductive phase of the immune response; and (B) effector sites, including epithelium and lamina propria (LP) of the intestinal mucosa. Endothelial cells of HEVs secrete chemokines that attract naive T cells. Endothelial chemokines trigger the activation of α4β7 integrin, which binds MAdCAM-1 on HEVs with high affinity, leading to the firm adhesion of rolling lymphocytes. The T cells then transmigrate across the endothelium into the T cell zone of the secondary lymphoid organs, where dendritic cells present antigen to the T cells. Antigen sampling in Peyer’s patches is controlled by a layer of specialized epithelial cells known as the follicular-associated epithelium. Peyer’s patch dendritic cells imprint gut-homing specificity on T cells (34), which become activated and upregulate integrin α4β7 expression. These activated T cells then migrate to the epithelium and lamina propria of the gut (B).