Induction of homotypic T cell adhesion by triggering of leukocyte function‐associated antigen‐1α (CD11a): differential effects on resting and activated T cells

Abstract

The leukocyte integrin LFA-1 (CD11a/CD18) plays a key role in many adhesive interactions involving cells of the immune system. Recently, it has been shown that LFA-1 is not only involved in cell adhesion, but that stimulation of LFA-1 can also contribute to cell activation. We now demonstrate that triggering of LFA-1 on T lymphocytes by monoclonal antibodies (mAb) against the LFA-1 alpha chain, but not against the LFA-1 beta chain, promotes cell adhesion. Induction of homotypic adhesion was only observed in T cells that had been pre-activated with anti-CD3 and not in resting peripheral blood T lymphocytes. The induced homotypic adhesion is mediated by LFA-itself, because it was inhibited by anti-LFA-1 beta mAb. This notion is supported by the temperature and divalent cation dependence which is characteristic of LFA-1-mediated adhesion. mAb against ICAM-1 (CD54) did not block LFA-1 alpha-induced adhesion. The sensitivity of LFA-1 alpha-induced adhesion to H7, which prevents the activation of protein kinase C and protein kinase A, and to cytochalasin B, which inhibits microfilament formation, suggests that the activation of the LFA-1 pathway through the LFA-1 alpha chain involves cell activation and requires an intact cytoskeleton.

Signaling through the LFA‐1 leucocyte integrin actively regulates intercellular adhesion and tumor necrosis factor‐α production in natural killer cells

“…Other cell surface antigens have been reported to upregulate LFA-1 activity when bound by the corresponding specific mAb, all of them presumably are signal transducer molecules able to activate the metabolic pathways involved in LFA-1 regulation [lo, 11,28,33,341. Different potentially overlapping molecular mechanisms may underlie HPlN-induced adhesion including: (a) a conformational change in LFA-1 as described for other integrins [3] and proposed for LFA-1 [32]; (b) a clustering of the molecule on the cell surface accounting for the facilitation of the adhesion process; c) a signal transduced by LFA-1 able to self-regulate its functional properties; this possibility is supported by the fact that HPlN mAb induced an increase in (Ca*+)i. Interestingly, HPlN brightly stained but failed to aggregate fresh unstimulated NK and Tcells; these data pointed out that lymphocytes required a preactivation to respond to the mAb, and are in agreement with other recent observations [35].…”

“…I n line with this is an increasing number of data suggesting an active role of LFA-1 in leukocyte activation . These phenomena are thought to involve phosphoinositide turnover and Ca2+ signaling [21], and t o be associated to cytoskeletal rearrangements [35,40]. We have observed that H P l N reproducibly triggered a transient increase in (Ca2+)i highly enhanced upon cross-linking of t h e antibody with an anti mouse IgG serum, suggesting that variation in (Ca2+)i might be one of the signals accounting for the costimulation of TNFa production, and for the induction of the homotypic adhesion.…”

Pharmacodynamic Monitoring of Calcineurin Inhibition Therapy: Principles, Performance, and Perspectives

“…It also acts as a costimulatory signal in T-cell interactions. 33 Two other surface activation receptors are CD69 and CD71. Activation-induced molecule (CD69) is present on activated but not resting T cells, and appears relatively early after T-cell activation.…”

The immune dysregulatory compound mercuric chloride induces integrin‐mediated T‐lymphocyte adhesion

“…Human peripheral blood obtained from healthy donors was used for isolation of peripheral blood mononuclear cells (PBMC) by density gradient centrifugation, using Ficoll‐Paque (Pharmacia Biotech, Uppsala, Sweden). T lymphoblasts were generated by culturing PBMC for 5–7 days in the presence of soluble OKT3 (mAb anti‐CD3) and of a cytokine mixture, that was obtained from activated PBMC, as described, 28 using RPMI culture medium (RPMI‐1640 supplemented with 10% heat‐inactivated fetal calf serum, 100 IU/ml penicillin, 100 µg/ml streptomycin, and 2 m m glutamin). The human Th0 cell clone ACC6 (kindly provided by Dr M. L. Kapsenberg, Amsterdam, the Netherlands), was stimulated every 14 days by allogeneic feeder cells and phytohaemagglutinin, as described, 29 and cultured in Iscove's modified Dulbecco's medium (Gibco BRL Life Technologies, Paisley, UK), supplemented with 10% heat‐inactivated normal human serum, 25 U/ml recombinant IL‐2 (Eurocetus, Amsterdam, the Netherlands), 100 IU/ml penicillin, 100 µg/ml streptomycin and 2 m m glutamin.…”