ITGAE - integrin subunit alpha E |Elisa - Clia - Antibody - Protein

Background

Integrin subunit alpha E, known as ITGAE, is a critical component of the immune system, particularly in regulating immune cell retention in epithelial tissues. ITGAE, often referred to as CD103 in immunological contexts, partners with the integrin beta 7 subunit to form the heterodimeric receptor αEβ7. This integrin is specifically expressed on subsets of immune cells, including mucosal T lymphocytes, dendritic cells, and natural killer (NK) cells, where it binds to E-cadherin, an adhesion molecule on epithelial cells. By binding E-cadherin, αEβ7 plays a critical role in localizing lymphocytes to epithelial tissues, particularly within the gut, skin, and lungs, where immune surveillance is essential. This adhesion mechanism enables αEβ7-expressing cells to provide targeted immune responses and maintain tissue integrity.

Protein Structure

The ITGAE gene encodes the αE integrin subunit, which is a transmembrane glycoprotein composed of 1160 amino acids and has a molecular weight of around 130 kDa. Integrins like αE are complex proteins with specific structural features enabling them to interact with ligands and support cellular adhesion functions:

Extracellular Domain:

• The extracellular portion of ITGAE is the largest component and contains several distinct structural motifs essential for its function, including an I domain. This domain is critical for binding to E-cadherin on epithelial cells, allowing αEβ7 to mediate cell-cell adhesion effectively.
• The αE subunit also contains a β-propeller domain with seven beta-sheet-rich blades that form a circular structure. This domain, common to integrins, supports ligand binding and can undergo conformational changes that regulate affinity.
• Calcium and magnesium-binding sites within the extracellular domain contribute to the stability and regulatory functions of the αEβ7 integrin complex.

Transmembrane Domain:

• The transmembrane region of the αE subunit is a short α-helical segment embedded within the lipid bilayer of the cell membrane. This region anchors the integrin to the cell surface and, in conjunction with the beta 7 subunit, is involved in transmitting conformational changes from the extracellular domain to the intracellular portion, allowing inside-out signaling.

Cytoplasmic Tail:

• The cytoplasmic tail of ITGAE interacts with intracellular adapter proteins and the cytoskeleton, facilitating cellular signaling and stability. The short cytoplasmic domain allows binding to cytoskeletal proteins and signaling molecules such as talin and kindlin, which are critical for integrin activation and signal transduction.

The αEβ7 heterodimer structure allows it to bind with high affinity to E-cadherin, effectively anchoring immune cells to epithelial surfaces and promoting the retention of lymphocytes in tissues.

Classification and Subtypes

ITGAE is a part of the integrin family, specifically within the alpha-integrin subunit group. Integrins are classified by their alpha and beta subunits, with different combinations conferring specific ligand-binding properties and tissue localization patterns.

Integrin Subunit Alpha E (αE):

• Heterodimer Pairing: ITGAE specifically pairs with the beta 7 subunit to form the αEβ7 complex.
• Ligand Specificity: This integrin binds primarily to E-cadherin, a calcium-dependent cell adhesion molecule expressed on epithelial cells.

Integrin Beta 7 (ITGB7):

• ITGB7 can pair with other alpha subunits, such as α4, to form α4β7, which binds to mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) for gut-specific homing of immune cells.

Function and Biological Significance

Tissue Retention of Immune Cells:

• The primary role of αEβ7 is to anchor immune cells, especially cytotoxic T cells, dendritic cells, and NK cells, to epithelial cells. This retention mechanism is crucial in tissues where immune surveillance and rapid immune responses are needed, such as the gut, lungs, and skin.

Immune Surveillance in Mucosal Sites:

• By binding to E-cadherin, αEβ7 promotes the localization of effector T cells in epithelial tissues, enhancing immune surveillance and the ability to rapidly respond to pathogens at barrier sites. αEβ7 plays a particularly important role in gut immunity, where it maintains a pool of resident T cells that can respond to bacterial and viral infections without the need for lymph node activation.

Role in Inflammation and Tissue Homeostasis:

• ITGAE expression is upregulated on T cells during inflammation, particularly in response to cytokines such as TGF-β, which drives the differentiation of T cells into tissue-resident memory T cells (Trm cells). These Trm cells contribute to tissue homeostasis by recognizing and eliminating infected or damaged cells and producing cytokines that maintain a controlled inflammatory response.

Regulation of Immune Response:

• The expression of ITGAE on regulatory T cells (Tregs) enables these cells to localize to mucosal surfaces and mediate immune suppression, preventing excessive inflammation and promoting immune tolerance in tissues exposed to environmental antigens.

Clinical Issues

Inflammatory Bowel Disease (IBD):

• ITGAE/αEβ7 is a critical integrin in gut-associated immunity, and its dysregulation is associated with inflammatory bowel disease, including Crohn's disease and ulcerative colitis. In IBD, increased expression of αEβ7 on lymphocytes may enhance their retention in inflamed mucosal tissue, exacerbating inflammation and contributing to the chronicity of the disease.
• Therapies targeting αEβ7 or its interaction with E-cadherin are under investigation for their potential to reduce inflammatory immune cell infiltration in the gut and alleviate symptoms of IBD.

Cancer and Tumor Microenvironment:

• In certain cancers, such as colorectal cancer, ITGAE expression has been linked to both pro-tumor and anti-tumor functions, depending on the cellular context. Tumor-infiltrating lymphocytes expressing ITGAE may help localize immune cells within the tumor microenvironment, enhancing anti-tumor immunity. Conversely, certain cancers may exploit αEβ7-E-cadherin binding to evade immune surveillance by trapping immune cells within the tumor.
• Increased ITGAE expression in regulatory T cells within tumors can also suppress effective immune responses against tumors, leading to immune escape and potentially promoting cancer progression.

Autoimmune Diseases:

• In autoimmune conditions, the dysregulated expression of ITGAE on immune cells may contribute to tissue-specific autoimmunity, as it promotes immune cell retention within affected tissues. For example, in autoimmune skin disorders, high levels of αEβ7 on T cells may facilitate prolonged immune cell presence within the skin, causing chronic inflammation.

Viral Infections:

• The retention of immune cells in tissues mediated by αEβ7 has implications for viral infections such as HIV, where high levels of αEβ7 on T cells in the gut mucosa may contribute to viral persistence by retaining HIV-infected cells within the gut, a major reservoir for the virus.

Summary

Integrin subunit alpha E (ITGAE), or CD103, is essential for immune cell adhesion to epithelial tissues, forming the αEβ7 complex that binds to E-cadherin. This interaction localizes immune cells to epithelial sites, particularly in the gut, lungs, and skin, where rapid immune responses are crucial. Structurally, ITGAE comprises an I domain for E-cadherin binding, a β-propeller domain, and a cytoplasmic tail that interacts with intracellular signaling proteins.

ITGAE is central to immune surveillance, inflammation, and tissue-specific immunity, with significant roles in conditions such as inflammatory bowel disease, cancer, and autoimmune diseases. By promoting immune cell retention within tissues, αEβ7 enables tissue-resident memory T cells to respond to infection or injury but can also exacerbate chronic inflammation in disease contexts. Therapeutic targeting of ITGAE and its interactions offers potential in managing inflammatory and immune-mediated diseases, highlighting its importance in immunology and clinical research.