Alpha 4 Beta 7: Structure and Mucosal Homing in T Cells

Integrins are essential for immune cell trafficking, and α4β7 plays a key role in directing T cells to mucosal tissues. By interacting with specific ligands, it facilitates migration to barrier sites like the intestines, ensuring an effective immune response. Understanding its function provides insight into gut immunity and diseases such as inflammatory bowel disease (IBD).

Given its role in targeting lymphocytes to mucosal surfaces, α4β7 is a focus of immunology research and therapeutic development.

Structure In T Cells

The α4β7 integrin is a heterodimeric transmembrane receptor composed of two subunits: α4 (CD49d) and β7 (ITGB7). These subunits associate non-covalently, forming an adhesion molecule critical for T cell migration. The α4 subunit contains an extracellular domain for ligand binding, while the β7 subunit contributes to intracellular signaling and cytoskeletal interactions. Together, they enable T cells to adhere to endothelial cells lining mucosal tissues, a process dependent on conformational changes in the integrin complex.

The extracellular domain of α4β7 shifts between inactive and active states, regulated by divalent cations like Mn²⁺ and Mg²⁺, which influence its affinity for mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Cryo-electron microscopy studies show α4β7 adopts a bent conformation in its resting state, reducing ligand affinity. Upon activation, it extends into an open conformation, enhancing adhesion. This flexibility allows T cells to transition between circulation and tissue residency.

The cytoplasmic domains of α4 and β7 interact with adaptor proteins such as talin and kindlin, linking the integrin to the actin cytoskeleton. These interactions enable integrin clustering and stable adhesions under shear stress. The β7 subunit contains a conserved GFFKR motif that modulates interactions with intracellular signaling molecules. Mutations in this region impair adhesion and migration, highlighting its structural importance in T cell function.

Expression Patterns In Lymphocyte Subsets

α4β7 expression varies across lymphocyte subsets, reflecting its specialized role in guiding immune cells to mucosal sites. Among T cells, it is highly expressed on memory CD4⁺ and CD8⁺ T cells primed in gut-associated lymphoid tissues (GALT). These cells acquire α4β7 expression during activation in Peyer’s patches and mesenteric lymph nodes, where dendritic cells imprint a mucosal-homing phenotype. Retinoic acid, a vitamin A metabolite, enhances α4β7 expression through nuclear receptor signaling. As a result, memory T cells primed in the gut retain long-term mucosal surveillance capabilities.

Regulatory T cells (Tregs) also express α4β7, contributing to immune homeostasis in the intestines. FoxP3⁺ Tregs preferentially migrate to the lamina propria, where they suppress excessive inflammation and maintain tolerance to commensal microbiota. Gut-resident Tregs exhibit higher α4β7 levels than their systemic counterparts, reinforcing its role in tissue-specific immune regulation. An imbalance of α4β7⁺ effector T cells and Tregs is linked to inflammatory pathologies.

B cells involved in mucosal immunity also display α4β7, particularly IgA-secreting plasma cells migrating from GALT to the intestinal lamina propria. This integrin facilitates their interaction with mucosal endothelial cells, enabling antibody secretion at barrier surfaces. B cell expression of α4β7 is regulated by the same factors influencing T cell homing, underscoring its role in coordinating mucosal immune responses.

Role In Mucosal Homing

T cells rely on α4β7 to navigate mucosal tissues. This process begins in secondary lymphoid organs, where antigen-presenting cells shape their migratory fate. Dendritic cells in Peyer’s patches and mesenteric lymph nodes expose T cells to environmental cues like retinoic acid, upregulating α4β7 expression. Once imprinted, these cells enter circulation equipped with adhesion molecules necessary for interaction with gut-associated vasculature.

The interaction between α4β7 and MAdCAM-1 is crucial for T cell recruitment. MAdCAM-1 is selectively expressed on high endothelial venules of intestinal tissues, creating a tissue-specific adhesion platform. This binding event stabilizes T cell rolling and adhesion under physiological blood flow conditions. Unlike integrins with broader tissue distribution, α4β7’s affinity for MAdCAM-1 ensures selective homing. Chemokines such as CCL25 enhance this process by engaging CCR9 on T cells, strengthening integrin activation.

Once bound to intestinal vasculature, T cells undergo transendothelial migration, exiting circulation to infiltrate mucosal tissues. This step is facilitated by cytoskeletal rearrangements within the T cell, driven by signaling cascades linked to the β7 subunit. The integrin’s ability to transition between low- and high-affinity states is essential for efficient extravasation. Additional retention signals, including interactions with extracellular matrix components, anchor these cells in place, supporting long-term residency.

Regulatory Mechanisms And Signaling

α4β7 function is tightly regulated by intracellular signaling pathways controlling activation, ligand affinity, and adhesion. These processes rely on conformational changes influenced by intracellular adaptors and signaling molecules. Inside the T cell, talin and kindlin bind to the β7 subunit’s cytoplasmic tail, shifting the integrin from a low- to high-affinity state. This switch enhances engagement with MAdCAM-1, facilitating firm adhesion and migration.

Upstream signaling further modulates α4β7 activity, particularly through G protein-coupled receptors (GPCRs) activated by chemokines like CCL25. Upon engaging CCR9, CCL25 triggers signaling cascades involving phosphoinositide 3-kinase (PI3K) and Rap1, a small GTPase that promotes integrin clustering. This inside-out signaling ensures α4β7 activation in response to chemotactic cues, optimizing T cell homing. Outside-in signaling occurs when α4β7 binds MAdCAM-1, initiating pathways that influence cytoskeletal reorganization and motility.

Relationship To α4β1

α4β7 shares structural and functional similarities with α4β1, another integrin involved in immune cell trafficking. Both contain the α4 subunit, allowing them to bind overlapping ligands, but their distinct β subunits confer unique adhesive properties. While α4β7 directs T cells to mucosal tissues via MAdCAM-1, α4β1 (VLA-4) binds to vascular cell adhesion molecule-1 (VCAM-1) and fibronectin, supporting migration to inflamed and non-mucosal tissues. This divergence enables compartmentalized immune surveillance.

The interplay between α4β7 and α4β1 influences T cell distribution, particularly under inflammatory conditions where expression levels shift in response to cytokine signaling. In chronic inflammatory diseases like IBD, increased α4β1 expression on circulating lymphocytes may compensate for dysregulated mucosal homing via α4β7. This shift alters immune cell dynamics, contributing to persistent inflammation by redirecting T cells to non-mucosal sites. Therapeutic interventions such as vedolizumab selectively block α4β7 to reduce gut-specific inflammation without broadly suppressing immune function. Understanding the balance between these integrins informs strategies for modulating lymphocyte migration in health and disease.