Integrin function

p2-integrins

Integrins participate in cell interactions in many tissues, including those of the immune system. Of the integrins specific to leukocytes, Mac-1 and pi 50,95 are largely confined to the cells of the myeloid lineage. These (32-integrins are present in cytoplasmic granules but are rapidly translocated to the membrane following exposure of myeloid cells to inflammatory stimuli such as cytokines and chemo-kines. Mac-1 has an impressive array of ligands, including iC3b, fibrinogen, factor X as well as ICAM-1, and the binding activities of pi50,95 largely reflect that of Mac-1. Mac-1 is also found in cis associations with a number of surface receptors, including FC7RIIA, FC7RIIIB, urokinase and LPS/LBP-bound CD14, and it is proposed that Mac-1 may function as a transducer of signals resulting from the binding of these associated receptors to their ligands. Interestingly pi 50,95 also binds FcyRIIIB and LPS/LBP-bound CD 14 and Petty and Todd have suggested that ligands may 'shuffle' between these two integrins during cell locomotion. The recently described otD(32 is highly expressed by tissue macrophages and so far is the only (32-integrin to bind exclusively to ICAM-3.

In contrast, LFA-1 is found on all leukocytes. It functions in antigen presentation between T ceils and different types of antigen-presenting cell where ICAM-3 may serve as an initial ligand; inhibition of T cell-mediated killing (but see next section); natural killer cell activity; neutrophil antibody-dependent cellular cytotoxicity; binding of tumor cells by activated macrophages and homotypic aggregation of proliferating leukocytes. The rapid response of memory T cells to antigen is facilitated by the presence of increased levels of LFA-1 and ligand ICAM-1, permitting enhanced cell-cell interactions. It is important to note that this increase in expression of adhesion receptors does not automatically cause elevated integrin activity. Triggering of T cells through specific receptors or with phorbol esters is necessary to bring about increased LFA-1 adhesion to ICAM-1. This control of receptor function through 'inside-out' signaling has the advantage that high avidity intercellular adhesion will occur onh when the involved cells are activated. The increase in avidity is thought to depend on either redistri bution of receptor in the membrane and/or conformational changes in LFA-1.

a4-integrins

The VLA antigens were first identified by Martin Hemler on T cells growing in long-term culture bur are known to be more widely distributed. In vivo VLA-4 (a43i) is expressed on early thymic precursor cells and is retained until the 'double-positive' CD4+8+ blast stage prior to the exiting of functionally mature 'single-positive' CD4 or CD8 T cells from the thymus into the circulation. Memory T cells and monocytes have enhanced levels of VLA-4, VLA-5 (a,[email protected]) and VLA-6(a6p,) and these receptors become activated like LFA-1 when these cells are triggered through the T cell receptor and are thought to function as the cells move within tissue compartments. The a4p7-integrin binds to fibronectin and VCAM-1 but is known as the mucosal homing receptor because it recognizes the mucosal addressin MAdCAM-1. The second p7-integrin, a^, is expressed by intraepithelial T cells and is the only integrin to recognize a member of the cadherin adhesion family, E-cadherin.

p3-integrins

The cytoadhesins ((3? family) are also represented on leukocytes. The integrin gpIIb/IIIa is exclusively found on megakaryocytes and platelets and, by its binding to fibrinogen, functions as the key receptor on platelets in the clotting cascade. Fibrinogen binding by gpIIb/IIIa is tightly controlled; it occurs only after activation with agonists such as thrombin and involves a conformational change in gpflb/IIIa (deduced from expression of ligand-induced binding site (LIBS) epitopes). Similar activation events permit gpIIb/IIIa to bind fibronectin or vWF, mediating the adhesion of platelets to endothelium or the subendo-thelial matrix. The other classical cytoadhesin, the VNR, is found on tissue culture-matured monocytes and is implicated in recognition of senescent or apop-totic leukocytes. This specialized form of phagocytosis ensures that dying cells are removed from tissues, limiting the damage caused by their potentially harmful contents.

Adhesion cascade

The cooperative action of integrins with the selectin adhesion receptors in successfully guiding leukocytes from the bloodstream across the endothelium and into injured tissue has been termed the adhesion cascade (Figure 2). It was initially thought that selectins alone were responsible for tethering leukocytes to stimulated endothelium bur it is now recognized that the ot4-integrins can also perform this role. In fact u integrins appear to be capable of participating in all stages of leukocyte transmigration, including leukocyte arrest on stimulated endothelium and movement across endothelium into the tissue space. LFA-1 and Mac-1 dominate as the integrins causing firm binding and cell flattening of cells on endothelium. Neutrophils rely only on LFA-1 and Mac-1 as thev lack nr integrins. Although chemokines arc attractive candidates as integrin activators, more proof is needed that they are major activators of a.,- or f32-integrins in this situation.

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