The role of calcium ions in initiating transformation of lymphocytes

Abstract

TRANSFORMATION of lymphocytes by antigens and by nonspecific mitogens (lectins and anti-immunoglobulin sera) is a consequence of the binding of the mitogen to specific receptors on the cell surface^1–3. The receptors rapidly form clusters (‘patches’) which may aggregate into polar ‘caps’⁴ at higher mitogen concentration. These events initiate a series of biochemical changes—enhanced uptake of ions and metabolites¹, increased cyclic GMP⁵, and increased metabolism of phosphatidyl inositol and other phospholipids (ref. 6 and V. C. M., M. J. Hayman and M. J. C., unpublished)—which culminate in DNA synthesis and mitosis 48–72 h later. Although the sequence, relative importance and control of these events is not yet defined, there is evidence for a primary role for Ca²⁺. Phaseolus vulgaris phytohaemagglutinin (PHA) initiates a slow accumulation of Ca²⁺ by lymphocytes^7,8 and its stimulation of DNA synthesis is inhibited by citrate⁹, EDTA (ref. 9) or EGTA (ref. 10). The inhibition is reversed by Ca²⁺. It has also been shown that inhibition by the low concentrations (1.4 mM) of EGTA used did not prevent binding of PHA (ref. 11). Although these results showed Ca²⁺ to be an important factor in initiation of transformation it was not clear whether influx of Ca²⁺ was the only or even the main consequence of the binding of PHA.