Evidence for an interleukin-independent pathway for human lymphocyte activation.

Abstract

Though lectin mitogen stimulation of T-cell proliferation is an interleukin 1-(IL 1), interleukin 2-(IL 2) dependent process, the calcium ionophore A23187 may be able to initiate T-lymphocyte proliferation by an additional pathway. That the action of A23187 is IL 1 independent was demonstrated by its ability to stimulate monocyte-depleted cells without the addition of exogenous IL 1. The IL 2 independence of A23187 was indicated by (i) the inability of exogenous IL 2 to augment A23187-induced proliferation and (ii) the inability of the monoclonal antibody anti-Tac (with specificity for the human IL 2 receptor) to inhibit proliferation mediated by A23187. By contrast, in cultures stimulated with the lectin mitogen phytohemagglutinin, additional IL 2 considerably increased proliferation, whereas anti-Tac routinely caused 60-90% inhibition. Although the ionophore caused some IL 2 production and resulted in IL 2 receptor expression, quantitative studies showed that our results could not be explained by excessive amounts of endogenous IL 2 interfering with the blockdng action of the antibody. Therefore, these data suggest that the action of A23187 as a human lymphocyte mitogen may be the result of at least two pathways-one dependent on the interleuidn-cell interactions and the other independent of these mediators.The importance of soluble mediators in the activation of T lymphocytes has become increasingly clear in the past several years (1-10). Since the demonstration in 1976 that a soluble factor in culture supernatants could support the continued growth of T cells in culture (1), the central role of interleukin 2 (IL 2) in the proliferation of human and murine T cells has been established by many investigators. The result of these studies has been several models describing the role of soluble mediators in T-lymphocyte activation by mitogens (4, 7, 10). A central tenet of one of these models is that monocytes are required for lectin mitogen stimulation because of a product (interleukin 1; IL 1) that they elaborate. Mitogen and IL 1 then together interact with T cells, resulting in the production of IL 2 (7, 10) and the acquisition of IL 2 receptors (11). However, it remains unclear whether this is the only means whereby proliferation of T lymphocytes can occur.To approach the possibility of an alternative pathway for Tcell activation that might be independent of IL 1 or IL 2, or both, we used the calcium ionophore A23187, which is mitogenic for human lymphocytes (12, 13). We present evidence that the ionophore is capable of stimulating monocyte-depleted human lymphocytes (MDC) to proliferate without added replacing factors [e.g., IL 1, 12-0-tetradecanoylphorbol 13-acetate (TPA)], thus suggesting that the action of A23187 is IL 1 independent. We also present evidence that the monoclonal antibody anti-Tac, which appears to identify the human IL 2 receptor (14-17) does not inhibit cultures stimulated by A23187, although this antibody is a potent inhibitor of activation induced by other mitogens or antigens. I...

Diltiazem inhibits transferrin receptor expression and causes G1 arrest in normal and neoplastic T cells.

“…The mobilization of calcium from intracellular stores and the import of extracellular calcium both occur during mitogenesis. In some cases a calcium ionophore may bypass requirements for tissue-specific growth factors such as IL-2 (17). Recent studies with calcium channel-blocking agents confirm earlier results with calcium chelators, demonstrating that the influx of extracellular calcium is necessary to * Corresponding author.…”

Expression of cell-cycle-dependent genes in phytohemagglutinin-stimulated human lymphocytes.

“…The results with c-myc are less clear, but it should be noted that c-myc too is detectable before the appearance of IL-2 mRNA. Since addition of IL-2 to MDC causes them to enter S phase, a plausible explanation is that alternative pathways exist for the entry of PHA-stimulated lymphocytes into S phase, as already proposed by Koretzky et al (50).…”

Recombinant interleukin 2 therapy in severe combined immunodeficiency disease.

“…Given that IL-2 mRNA was absent in our patient, it is possible that the patient's cellular defect may reside in inositol phospholipid metabolism leading to unresponsiveness of the T cells; such could be the case even though some T-cell activation events could occur-e.g., partial IL-2R and some degree of response to Con A and PWM (38,39). Alternatively, T-cell proliferation in this patient may have been possible via an interleukin-independent pathway for lymphocyte activation (40).…”

“…-The child tolerated these infusions well. Dosage was then increased to 40,000 units-kg-l day1 i.v., to be infused over a 6-hr period. With the first infusion at this dose,' the patient.…”