Transmembrane Ion Fluxes during Activation of Human T Lymphocytes: Role of Ca²⁺, Na⁺/H⁺ Exchange and Phospholipid Turnover

Abstract

The importance of increases in [Ca2+]i, stimulation of Na+/H+ exchange, and turnover of membrane phospholipids as signals for mitogen-induced activation of human T cells has been reviewed. In the presence of optimal concentrations of lectin and appropriately presented antigen, T cells increase [Ca2+]i, secrete IL2, express IL2 receptors and later divide. An increase in [Ca2+]i is critical for IL2 secretion in contrast to the requirements for IL2 receptor expression and IL2-IL2 receptor interaction. Treatment of T cells with TPA appears to bypass the requirement for an increase in [Ca2+]i for IL2 secretion and cell proliferation, indicating that various mitogens can trigger T cells through both [Ca2+]i-dependent and [Ca2+]i-independent pathways. Influx of Ca2+ from the extracellular milieu appears essential for the induced increase in [Ca2+]i associated with IL2 secretion. These increases in [Ca2+]i, which are correlated with the degree of lymphoproliferation and IL2 secretion, are sensitive to changes in membrane potential. The changes in [Ca2+]i are not mediated by the opening of voltage-gated K+ channels but the nature of the potential-sensitive event remains to be determined. The membrane potential effects may be mediated through the gating of a putative Ca2+ channel or by affecting the inward electrochemical Ca2+ gradient. It is clear that lymphoid cells of both T and B lineage possess a functional Na+/H+ antiport, which plays a central role in the regulation of pHi. It is also generally agreed that the antiport can be stimulated by mitogens, co-mitogens and by agents that induce differentiation. The meaning of this stimulation is not, however, entirely understood. It may be an essential signal or link in the series of events triggered by the binding of ligands to their membrane receptors. Alternatively, it may represent an ancillary event, intended to increase H+ ejection in anticipation of an increased metabolic rate. Finally, a third possible reason for the stimulation of Na+/H+ exchange could be to increase the osmotic content of the cells, inducing cell swelling that may be an early requirement for cellular growth. Indeed, amiloride-sensitive cellular swelling has been detected electronically following treatment of T lymphocytes with TPA (Grinstein et al. 1985a). PHA is a potent activator of phosphatidylinositol hydrolysis. In other cell types, receptors are coupled to phospholipase C by a G protein(s). However, the transducing mechanism in human peripheral blood lymphocytes does not appear to be a pertussis toxin-sensitive G protein(s).(ABSTRACT TRUNCATED AT 400 WORDS)

Differential Regulation of the Overlapping Kaposi's Sarcoma-Associated Herpesvirus vGCR (orf74) and LANA (orf73) Promoters

“…The identification of such putative elements is currently ongoing. Since TPA induces proliferation in lymphoid cells (13) and in the BCBL-1 cell line induces cellular as well as KSHV replication, we conclude that in this cell type the LANAp promoter is not cell cycle regulated.…”

Lidocaine depresses splenocyte immune functions following trauma-hemorrhage in mice

“…Because all of these signaling pathways are upregulated via TCR activation, we believe that the above-mentioned studies support our conclusion of suppressed TCR-dependent pathways. In addition, Gelfand et al (13) reported that intracellular Ca 2ϩ release is critical for IL-2 secretion and cell proliferation of human T lymphocytes. This report also supports our conclusion that lidocaine inhibits IL-2 secretion and splenocyte proliferation via suppression of TCR activation and the downstream effects of this receptor.…”

Calcium-mediated inhibition of phorbol ester and Tax trans-activation of the human T cell leukaemia virus type 1

“…2b) and the sustained plateau is prevented by EGTA which chelates extracellular Ca ~+ (Fig. 2 c) (Alcover et al, 1987;Finkel et al, 1987;Gelfand et al, 1987).…”

“…Ionomycin enhances both the release of Ca 2÷ from intracellular stores and the influx of Ca 2÷ from the extracellular environment (Clevers et al, 1988;Gardner, 1989;Gelfand et al, 1987). Thus a pathway that enhances the free Ca 2÷ concentration within the cell may create conditions unfavourable for virus expression.…”