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)

Deoxyguanosine is selectively cytotoxic to leukemic cells from patients with T-acute lymphoblastic leukemia (T-ALL), whereas all other leukemic cell types were significantly less sensitive. Arabinosylguanine, a deoxyguanosine analog resistant to cleavage by purine nucleoside phosphorylase, is a more potent inhibitor of DNA synthesis in T- leukemic cells than deoxyguanosine and retains a selective cytotoxic activity for T-leukemic cells. Deoxyguanosine and arabinosylguanine are phosphorylated to deoxyGTP and arabinosylGTP, respectively, by T cells but not by other cell types. The phosphorylation and the cytotoxicity of arabinosylguanine are prevented by deoxycytidine. The selectivity of arabinosylguanine for malignant T cells, the exquisite sensitivity of these cells to the drug, and the failure of PNP to cleave the nucleoside indicate its potential in the treatment of T-ALL.

We have used the T-cell mitogen Staphylococcus aureus protein A (SpA) to study the role of monocytes in the early events of T-lymphocyte activation. The mitogenic response of human peripheral blood mononuclear cells (PBM) was compared to the response of populations enriched for T cells by E-rosetting (PBM-E+). In response to SpA, the [3H]thymidine uptake of PBM-E' was reduced by 80% compared to PBM. The reduced response of PBM-E' was completely restored by the addition of irradiated PBM-E-or the monocyte-like human cell line U-937 but not by addition of irradiated PBM-E'. A direct interaction of SpA with monocytes is important since proliferative responses could be generated by preincubation of U-937 with SpA followed by washing and subsequent addition to PBM-E+; incubation of PBM-E+ with SpA followed by washing and subsequent addition of U-937 did not result in a proliferative response. To further delineate the role of the monocyte, we examined the ability of soluble SpA, U-937, or U-937 preincubated with SpA to trigger Ca2+ flux into T lymphocytes, an early step in initiation of the proliferative response. SpA-pretreated U-937, but neither SpA nor monocytes alone, triggered Ca2+ movement into the T lymphocytes. This defines a new role for the monocyte in the early events of T-lymphocyte activation.The monocyte/macrophage is thought to have an important accessory role in T-lymphocyte proliferative responses to antigens and mitogens (1)(2)(3)(4)(5), but the precise mechanisms of monocyte action and their relationship to other early steps in lymphocyte activation are unclear. Proposed monocyte functions include (i) presentation of antigen or mitogen (6), (it) antigen processing (7,8), and (iii) secretion of lymphostimulatory molecules (e.g., interleukin 1) perhaps in concert with antigen presentation (9, 10). It has been difficult to separate clearly these functional properties by using in vitro systems, which usually measure lymphocyte proliferation occumng 72 hr after the initial activating event.Further delineation of the role of monocytes in lymphocyte activation requires identification and measurement of events occurring in the lymphocyte within minutes after activation. Studies of lectin-stimulated mitogenesis have identified such an event: lectin binding triggers a rapid influx of Ca2+ (11)(12)(13)(14)(15), which leads to the formation of an intracellular Ca2+-calmodulin complex (16). The changes in intracellular Ca2' appear to be obligatory early steps in the metabolic cascade leading eventually to DNA synthesis and cell division.In the present study, we have used a monocyte-dependent T-cell mitogen, Staphylococcus aureus protein A (SpA), to examine the participation of monocytes in the induction of Ca2+ movement across T-lymphocyte membranes. Monocytes preincubated with SpA trigger a rapid influx of Ca2+ into lymphocytes, whereas neither SpA nor monocytes alone trigger Ca2+ movement. These studies define a new role for the monocyte in the early events of T-lymphocyte activation. MATERIALS AND ...

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