Integrins are widely expressed cell surface adhesion molecules that mediate cell-extracellular matrix and cell-cell interactions. Integrins are the principal receptors on animal cells for binding most  like collagens, fibronectin and laminins. T cells have little apparent adhesion to integrin ligands. However, upon activation through T cell receptor or chemokine receptors, a cascade of signaling events leads to enhanced integrin functionality, known as “inside-out” signaling. it involves the translocation of proteins to integrin cytoplasmic domains and the assembly of multiprotin complexes. The formation of these complexes results in activation and clustering of integrins, thus enhancing both affinity and avidity of integrins for their ligands.

Integrins are cell adhersion receptors that transmit bidirectional signals across the plasma membrane and link the extracellular enviornment of a cell to the actin cytoskeleton. The conformation of the integrin extracellular domain and its affinity for ligand are dynamically regulated by a process termed “inside-out signaling”. Rapid upregulation of adhesiveness of integrins on platelets and white blood cells mediates homostasis and luekocyte trafficking to sies of inflammation. By coupling to the actin cytoskeleton, integrins promote firm adhesion and provide traction for laeml-lipodium protrusion and locamotion. (US 2010/0167418). 

Structure:

Integrins are transmembrane alpha-beta heterodimers and at least 18 alpha and eight beta subunits are knonw in human, generating 24 heterodimers. The alpha and beta subunits have distinct domain structures, with extracellular domains from each subunit contributing to the ligand-binding site of the hterodimer. Examples of integrins include alpha4beta7. (Singh, US 16/536, 777, published as US 2020/0088749). 

Integrins are composed of 2 noncovalently associated transmembrane glycoprotein subunits called alpha and beta. Integrins have been organized into eight distinct subfamilies based on beta subunit assocations. Members of the beta 1 subfamily (also called VLA proteins) each contain the beta1 subunit in association with one of at least nine difference alpha subunits. In the beta2 subfamily, there are 3 distinct alpha subunits which associate with beta2 (CD11/CD18). The other groups associated with the beta3-beta8 subfamilies have various roles and functions.

Alpha-4 Integrin family: 

The α4 integrin family includes one of the most broadly expressed integrins, α4β1, and two of the most specialized integrins, α4β7 and α9β1. Unique among integrins, α4β7 is a homing receptor that targets lymphocytes and specific leukocyte subsets in the bloodstream to mucosal tissues, especially the gut. The primary ligand for α4β7-mediated homing is mucosal adhesion molecule-1 (MAdCAM-1), an addressin with two immunoglobulin superfamily (IgSF) domains and a mucin-like stalk that is specifically expressed on Peyer’s patch high endothelial venules and postcapillary venules in lamina propria. (J. Cell Biol. 2012, 196(1)). 131-146). 

Regulation of Integrin Expression: 

Integrin binding to their ligands depend on extracellular divalent cations like Ca2+ reflecting the presence of divalent cation binding domains in the extracellular part of the subunits. 

Integrins bind to a matrix protein outside the cell and to the  via an anchor protein inside the cell. The binding to their ligands is of low affinity but high capacity. (binding depends on a large number of weak adhesions). The clustering of integrins at sites of contact with the matrix can activate intracellular signaling pathways. Many of the signaling functions of integrins depend on a cytoplasmic protein tyrosine kinase called focal adhesion kinase (FAK). When integrins cluster at sites of cell-matrix contact, FAK is recruited to focal adhesions by intracellular anchor proteins such as talin or paxillin. The clustered FAK molecules cross phosphorylate each other on a specific tyrosine for members of the Src family of cytoplasmic .

A cell can also control integrin ligand interactions from within (inside out signaling) which allows regulated adhesion. This is important for example with T lymphocytes where the weak binding of a T lymphocyte to its specific antigen on the surface of an antigen presenting cell triggers intracellular signaling pathways that activate its integrins. The activated integrins enable the T cell to remain in contact long enough to become fully stimulated.

Integrins and Disease: 

During adhesion and transmigration, integrins of the beta1 and beta2 family, such as VLA4 (alpha4-beta1) or LFA-1 (alphaLbeta2), bind to their endothelial counter-receptors vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, respectively. EAE: Numerous studies have shown that adhesion of lymphocytes to inflamed brain vessels during EAE is mainly mediated by the VLA-4-VCAM-1 system, although there is also evidence pointing to the role of the LFA-1-ICAM-1 interaction. 

Atherosclerosis: Vascular cell adhesion molecules determine which type of luekocytes are recruited by selectively expressing specific adhesion molecules uch as vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and E-selectin. Subsequent conversion of leucocytes to foramy macrophages results in the synthesis of a wide variety of inflammatory cytokines, growth factors and chemoattractants that help popagate the leukocyte and platelet recruitment, smooth muscle cell proliferation, endothelial cell activation and extracellular matrix synthesis characteristic of maturing atherosclerotic plaque. 

HIV: The HIV cell surface glycoprotein, gp120, was shown to directly bind alpha4beta7 potentially facilitating HIV entrance into CD4 T cells. Several but not all integrin blocking antibodies reduced viral replication in CD4 T cell cultures.

Therapeutics: 

Natalizumab is a humanized anti-alpha4 integrin antibody that is approved for treatment of both MS and Crohn’s disease.

Vedolizumab is a gut-specific, alpha4beta7 integrin neutralizing mAb which does not affect peripheral blood cell counts and appears to lack systemic effects. 

(Singh, US 16/536, 777, published as US 2020/0088749).