The vitronectin receptor (αVβ3) as an example for the role of integrins in T lymphocyte stimulation

Abstract

Integrins are a family of cell surface receptors which mediate the adhesion of cells to each other or to extracellular matrix (ECM) proteins. The interaction of integrins with their ligands or counter-receptors was initially considered to be a one-way process in that cells actively regulate the interaction of integrins with their ligands ('inside-out signal'). In contrast, it was not obvious that cells would receive a signal from the outside via the integrin heterodimers following ligand binding ('outside-in signal'). Recent evidence increasingly supports the active role of integrins in cell activation and proliferation. Many reports describe the effects of integrin-mediated signaling in lymphoid cells. Our studies of gamma/delta T cells, expressing the beta 3 integrin vitronectin receptor (VNR), reflect some of the consequences this active interaction between lymphocytes and the ECM could have for T cell activation and differentiation. The VNR has been described as a T cell costimulatory molecule. We recently reported that the VNR has the potential to stimulate cytokine secretion in T cell hybridomas without involvement of T cell receptor-mediated signals. Further studies demonstrated tyrosine phosphorylation of proteins following VNR cross-linking and the interaction of the VNR with protein kinases. Intensive research focuses on the signal transduction mechanisms of integrins and their interaction with other costimulatory or activation molecules. This knowledge is important to better understand the role of adhesion molecules, the ECM, and the cellular microenvironment for lymphocyte activation and differentiation.

Prostaglandin E2 Promotes Integrin αVβ3-dependent Endothelial Cell Adhesion, Rac-activation, and Spreading through cAMP/PKA-dependent Signaling

“…For example, an increase in cAMP levels was shown to promote adhesion of immature thymocytes to fibronectin (41), to inhibit adhesion of mature T lymphocytes to fibronectin (42), and to suppresses leukocyte adhesion and migration in response to chemoattractants (43). Our findings indicate that, in endothelial cells, an elevation of cAMP accelerates ␣ V ␤ 3 -mediated adhesion and promotes Racdependent spreading via activation of PKA.…”

Hybridomas Expressing γδ T‐Cell Receptors Respond to Cardiolipin and β2‐Glycoprotein 1 (Apolipoprotein H)

“…The spontaneous cytokine production also depends on the VNR. The VNR, originally described as an anchoring integrin [48], also mediates cell‐to‐cell interactions in the phagocytosis of apoptotic cells by macrophages [49, 50] and participates as a coreceptor in T‐cell activation [51, 52]. In the apoptotic process, serum factors such as thrombospondin [53] or von Willebrand factor bind to the dying cells and serve as ligands for the VNR and CD36 [54].…”

Cellular Receptors and Hantavirus Pathogenesis

“…~3 integrins are prominent cell surface receptors on endothelial cells and platelets that mediate platelet activation, endothelial cell adherence, and regulate capillary integrity (CHERESH 1987;HAWIGER 1995;GERBER et al 1996;HALVORSON et al 1996;HYNES et al 1996;SUEHIRO et al 1996;SUGIMORI et al 1997;VEINOT et al 1999). ~3 integrins include two members, (1IIb~3 (CD41/CD61) and (lv~3, (CD51/CD61) which mediate a diverse group of cellular interactions and signaling responses (CHERESH 1987;HYNES 1992;SHATTIL et al 1994;SCHWARTZ et al 1995;.…”

“…(lv~3 is found on platelets, a number of immune cells, and endothelial cells, and mediates interactions with a variety of cells and ligands (CHARO et al 1990;SUGIMORI et al 1997). ~3 integrins on endothelial cells and platelets play central roles in maintaining capillary integrity (CHERESH 1987;HAWIGER 1995;GERBER et al 1996;HALVORSON et al 1996;HYNES and WAGNER 1996;SUEHIRO et al 1996;SUGIMORI et al 1997;Wu et al 1998;VEINOT et al 1999). Alterations in CXv~3 integrin binding permits increased transcapillary fluid fluxes and alter the hydrodynamics of capillaries CHAWIGER 1995;TSUKADA et al 1995;MOGFORD et al 1996;HODIVALA-DILKE et al 1999;.…”