Regulatory properties of LFA-1 α and β chains in human T-lymphocyte activation

Abstract

Lymphocyte function-associated antigen-1 (LFA-1) is a heterodimer composed of an alpha and beta chain that is expressed on the surface of most leukocytes and is an essential molecule for adhesion reactions between cells participating in the immune response. A putative ligand for LFA-1 is the intercellular adhesion molecule ICAM-1 (refs 3-5). Leukocyte adhesion abnormality is found in patients with LFA-1 deficiency. It is not clear whether binding of ligand to the LFA-1 molecule merely spatially orientates cells towards each other or can also induce signals that regulate cell activation and differentiation. We have recently developed a T-cell proliferation assay which uses immobilized anti-CD3 monoclonal antibodies as stimulant and is independent of LFA-1-mediated cellular adhesion. As there is no interference by anti-LFA-1 monoclonal antibodies with the adhesion-dependent activation steps, this T-cell activation system allows us to investigate whether transmembrane signals are induced by binding of ligand to LFA-1 on T cells. Our data indicate that binding of ligand to LFA-1 results in the transduction of regulatory signal across the plasma membrane, rather like other molecules (CD2, CD4, CD8) (refs 8-11) with signal-modifying properties involved in the adhesion of T cells to target/stimulator cells. Indeed, adhesion molecules might generally be important in signal transduction, even in cells not belonging to the immune system.

Cysteine protease cathepsin X modulates immune response via activation of β2 integrins

“…15,34,35 As mentioned previously, Mac-1 activity interferes with LFA-1 mediated aggregation 30 and it has been proposed that dysregulated adhesion and formation of immunological synapse caused by Mac-1 activity might explain down-regulated T-cell activation. 15 In this regard, it has been proposed that via constitutively active Mac-1 on macrophages, in contrast to functionally inactive Mac-1 on dendritic cells, antigen presentation in vivo is restricted to dendritic cells.…”

Interaction of leukocyte integrins with ligand is necessary but not sufficient for function.

“…There are several possible explanations for the inhibitory effects of this mAb. In some studies, mAbs to the 02 subunit of leuko-1533 cyte integrins have been shown to transduce negative regulatory signals to T cells (van Noesel et al ., 1988) and a similar mechanism might be operative for mAb 24 . Alternatively, mAb 24 might be cytotoxic for functioning cells .…”

“…One explanation might be that mAb 24 induces intracellular signals, enabling LFA-1 to combine with ligand with increased avidity. Such activity has been suggested for other LFA-1 a subunit mAbs that enhance proliferation, rather than inhibit function (van Noesel, 1988;Carrera et al ., 1988;Wacholtz et al . 1989;Pardi et al ., 1989).…”

Induction of LFA-1-mediated homotypic adhesions in promonocytic U-937 cells occurs independently of cell differentiation

“…This adhesion of monocytic cells is mediated by the LFA-1 and ICAM-1 molecules [10,11]. Since binding of ligand to LFA-1 is required for T cell function [12] and the existence of regulatory signals conveyed by LFA-1 has been suggested for T lymphocytes [13,14], we have analyzed in this report the possible occurrence of cell differentiation in the human promonocytic U-937 cells when these cells are induced to agregate via LFA-1/IC A M -l by a mAb specific for LFA-1.…”