Induction of DNA synthesis in human lymphocytes: interaction between non-specific mitogens and antigens.

Human blood lymphocytes stimulated with non-specific mitogens, such as PHA, ALS and streptolysin, responded with DNA synthesis only to certain optimal doses of the mitogens, higher and lower doses failing to stimulate the cells. With ALS only a 100-fold difference in concentration covered the entire dose range. Specific antigens on the other hand were stimulating over a 10,000-fold difference in concentration. The simultaneous stimulation of lymphocytes with two non-specific mitogens resulted in antagonistic or synergistic effects. Antagonism was found when two mitogens were added in optimal concentrations, whereas synergism occurred when both were present in suboptimal concentrations. Non-specific mitogens in high concentrations abolished induction of DNA synthesis by specific antigens, whereas they increased the response to antigen when they were added in low, by themselves non-stimulating, concentrations. The mixed lymphocyte culture reaction was found to abolish stimulation caused by non-specific mitogens added 3 days later. The findings suggest that individual lymphocytes respond with DNA synthesis after contact with a stimulus only when a threshold number of sites on the surface has been triggered. When the number of triggered sites is increased above a certain higher threshold, the lymphocytes fail to respond. Furthermore, the lymphocytes do not discriminate between the quality of the sites triggered, but only between the number of triggered sites, disregarding the nature of the stimulus. Finally, sensitized and presumably thymus-processed lymphocytes, confronted with antigen appear to influence other non-antigen recognizing cells, presumably by releasing some factors. These factors are capable of stimulating non-antigen-recognizing cells or to make them refractory to stimulation by subsequently added mitogens.